ORCID Profile
0000-0001-8908-6071
Current Organisations
Peter MacCallum Cancer Centre
,
Peter MacCallum Cancer Institute
,
Victorian Comprehesive Cancer Centre
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Publications
A multisite blinded study for the detection of BRAF mutations in formalin-fixed, paraffin-embedded malignant melanoma.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2013
DOI: 10.1038/SREP01659
Preclinical FLT-PET and FDG-PET imaging of tumor response to the multi-targeted Aurora B kinase inhibitor, TAK-901
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.NUCMEDBIO.2013.11.001
Abstract: The Aurora kinases play a key role in mitosis and have recently been identified as attractive targets for therapeutic intervention in cancer. The aim of this study was therefore to investigate the utility of 3'-[(18)F]fluoro-3'-deoxythymidine (FLT) and 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) for assessment of tumor response to the multi-targeted Aurora B kinase inhibitor, TAK-901. Balb/c nude mice bearing HCT116 colorectal xenografts were treated with up to 30mg/kg TAK 901 or vehicle intravenously twice daily for two days on a weekly cycle. Tumor growth was monitored by calliper measurements and PET imaging was performed at baseline, day 4, 8, 11 and 15. Tumors were harvested at time points corresponding to days of PET imaging for analysis of ex vivo markers of cell proliferation and metabolism together with markers of Aurora B kinase inhibition including phospho-histone H3 (pHH3) and senescence associated β-galactosidase. Tumor growth was inhibited by 60% on day 12 of 30mg/kg TAK-901 therapy. FLT uptake was significantly reduced by day 4 of treatment and this corresponded with reduction in bromodeoxyuridine and pHH3 staining by immunohistochemistry. All biomarkers rebounded towards baseline levels by the commencement of the next treatment cycle, consistent with release of Aurora B kinase suppression. TAK-901 therapy had no impact on glucose metabolism as assessed by FDG uptake and GLUT1 staining by immunohistochemistry. FLT-PET, but not FDG-PET, is a robust non-invasive imaging biomarker of early HCT116 tumor response to the on-target effects of the multi-targeted Aurora B kinase inhibitor, TAK-901. This is the first report to demonstrate the impact of the multi-targeted Aurora B kinase inhibitor, TAK-901 on tumor FLT uptake. The findings provide a strong rationale for the evaluation of FLT-PET as an early biomarker of tumor response in the early phase clinical development of this compound.
The state of melanoma: challenges and opportunities
Publisher: Wiley
Date: 17-04-2016
DOI: 10.1111/PCMR.12475
Prognostic Significance of p16INK4A and Human Papillomavirus in Patients With Oropharyngeal Cancer Treated on TROG 02.02 Phase III Trial
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-09-2010
Abstract: To determine the prognostic importance of p16 and human papillomavirus (HPV) in patients with oropharyngeal cancer treated on a phase III concurrent chemoradiotherapy trial. Patients with stage III or IV head and neck squamous cell cancer were randomly assigned to concurrent radiotherapy and cisplatin with or without tirapazamine. In this substudy, analyses were restricted to patients with oropharyngeal cancer. p16 was detected by immunohistochemistry, and HPV was detected by in situ hybridization and polymerase chain reaction. Slides were available for p16 assay in 206 of 465 patients, of which 185 were eligible, and p16 and HPV were evaluable in 172 patients. One hundred six (57%) of 185 were p16-positive, and in patients evaluable for both p16 and HPV, 88 (86%) of 102 p16-positive patients were also HPV-positive. Patients who were p16-positive had lower T and higher N categories and better Eastern Cooperative Oncology Group (ECOG) performance status. p16-positive tumors compared with p16-negative tumors were associated with better 2-year overall survival (91% v 74% hazard ratio [HR], 0.36 95% CI, 0.17 to 0.74 P = .004) and failure-free survival (87% v 72% HR, 0.39 95% CI, 0.20 to 0.74 P = .003). p16 was a significant prognostic factor on multivariable analysis (HR, 0.45 95% CI, 0.21 to 0.96 P = .04). p16-positive patients had lower rates of locoregional failure and deaths due to other causes. There was a trend favoring the tirapazamine arm for improved locoregional control in p16-negative patients (HR, 0.33 95% CI, 0.09 to 1.24 P = .13). HPV-associated oropharyngeal cancer is a distinct entity with a favorable prognosis compared with HPV-negative oropharyngeal cancer when treated with cisplatin-based chemoradiotherapy.
Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells
Publisher: American Association for Cancer Research (AACR)
Date: 12-2011
DOI: 10.1158/1541-7786.MCR-11-0312
Abstract: DNA-dependent protein kinase (DNA-PK) plays a pivotal role in the repair of DNA double-strand breaks (DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human cancer cells. We find that BEZ235, a novel inhibitor of DNA-PK and phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced DSB repair resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Importantly, radiation enhancement by BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive β-galactosidase staining, G2–M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated cytokine secretion. Because this senescence response to BEZ235 is accompanied by unrepaired DNA DSBs, we examined whether selective targeting of DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of DNA-PK, but not PI3K or mTORC1, delays DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of BEZ235. Thus, in the context of radiation treatment, our data indicate that inhibition of DNA-PK is sufficient for the induction of accelerated senescence. These results validate DNA-PK as an important therapeutic target in irradiated cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by DNA-PK blockade. Mol Cancer Res 9(12) 1696–707. ©2011 AACR.
Clinical and palliative care outcomes for patients of poor performance status treated with antiprogrammed death-1 monoclonal antibodies for advanced melanoma.
Publisher: Wiley
Date: 29-06-2017
DOI: 10.1111/AJCO.12702
Abstract: Antiprogrammed death-1 antibodies (anti-PD1) have response rates of 40% in metastatic melanoma. Patients with poor performance status (PS) were excluded from clinical trials, yet use of anti-PD1 is widespread in clinical practice. Literature regarding clinical and palliative care outcomes in patients with poor PS treated with anti-PD1 is lacking. Retrospective review of outcomes for all patients with advanced melanoma treated with anti-PD1 between 2012 and June 2015 at Peter MacCallum Cancer Centre, a tertiary specialist cancer center in Australia. Between 2012 and 2015, 91 patients received anti-PD1: median age 63, 65% males, 77% elevated LDH>1xULN (37/48 patients). Fifty-eight patients had baseline ECOG PS of 0-1 (64%), 24 patients ECOG PS 2-3 (26%) and ECOG PS was not recorded in nine patients (10%). Median overall survival (OS) for the ECOG PS 0-1 group was 19.5 months and 1.8 months for ECOG PS 2-3 (HR 5.5 95% CI, 9.1-50.3 P = 0.0001). Tumor response was 23/58 (39%) in ECOG PS 0-1, 2/16 (12%) in ECOG PS 2 and 0/8 in ECOG PS 3. Toxicity did not differ between different groups. ECOG PS 2-3 patients were more likely to be treated and hospitalized within the last month of life compared to ECOG PS 0-1 patients, RR 1.75 (95% CI, 1.04-2.56, P = 0.019) and RR 1.73 (95% CI, 1.10-2.16, P = 0.009), respectively. ECOG PS 2-3 patients were more likely to die in an acute hospital RR 2.68 (95% CI, 1.17-6.51, P = 0.016). Patients with poor baseline PS have a significantly lower OS and reduced response to anti-PD1. Further quality of life and palliative care research is needed.
Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma
Publisher: Massachusetts Medical Society
Date: 13-11-2014
In response to Drs. Krause, Baumann, and Thames
Publisher: Elsevier BV
Date: 09-2003
AKT Promotes rRNA Synthesis and Cooperates with c-MYC to Stimulate Ribosome Biogenesis in Cancer
Publisher: American Association for the Advancement of Science (AAAS)
Date: 30-08-2011
DOI: 10.1126/SCISIGNAL.2001754
Abstract: In addition to promoting translation, AKT also stimulates protein synthesis and cell growth by enhancing ribosome biogenesis.
Pathology of Melanoma
Publisher: Springer International Publishing
Date: 2017
Melanoma
Publisher: Springer International Publishing
Date: 2017
Targeted Therapies for Cutaneous Melanoma
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.HOC.2014.02.003
Abstract: Melanoma is resistant to cytotoxic therapy, and treatment options for advanced disease have been limited historically. However, improved understanding of melanoma driver mutations, particularly those involving the mitogen-activated protein kinase pathway, has led to the development of targeted therapies that are effective in this previously treatment-refractory disease. In cutaneous melanomas with BRAF V600 mutations the selective RAF inhibitors, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, have demonstrated survival benefits. Early signals of efficacy have also been demonstrated with MEK inhibitors in melanomas with NRAS mutations, and KIT inhibitors offer promise in melanomas driven through activation of their target receptor.
Management of Melanoma
Publisher: Springer International Publishing
Date: 2017
Loss of CDKN 2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK 4/6 inhibitor PD 0332991 in melanoma cell li
Publisher: Wiley
Date: 06-03-2014
DOI: 10.1111/PCMR.12228
Abstract: We have investigated the potential for the p16-cyclin D-CDK4/6-retinoblastoma protein pathway to be exploited as a therapeutic target in melanoma. In a cohort of 143 patients with primary invasive melanoma, we used fluorescence in situ hybridization to detect gene copy number variations (CNVs) in CDK4, CCND1, and CDKN2A and immunohistochemistry to determine protein expression. CNVs were common in melanoma, with gain of CDK4 or CCND1 in 37 and 18% of cases, respectively, and hemizygous or homozygous loss of CDKN2A in 56%. Three-quarters of all patients demonstrated a CNV in at least one of the three genes. The combination of CCND1 gain with either a gain of CDK4 and/or loss of CDKN2A was associated with poorer melanoma-specific survival. In 47 melanoma cell lines homozygous loss, methylation or mutation of CDKN2A gene or loss of protein (p16(INK) (4A) ) predicted sensitivity to the CDK4/6 inhibitor PD0332991, while RB1 loss predicted resistance.
Targeting oncogenes in advanced melanoma.
Publisher: Springer Science and Business Media LLC
Date: 2012
Dermatofibrosarcoma protuberans: a surgical disease with a molecular savior
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2006
Reply to ‘Comment on ‘Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy’’
Publisher: Springer Science and Business Media LLC
Date: 21-03-2017
DOI: 10.1038/BJC.2017.59
RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-01-2012
Abstract: RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation. Four international centers contributed 237 KA or cSCC tumor s les from patients receiving an RAF inhibitor (either vemurafenib or sorafenib n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each s le was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric–based genotyping platform. Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non–RAF inhibitor (21.1% v 3.2% P .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1% immunosuppression, 18.9% and spontaneous, 17.6% P = not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v 70 years), and sex had no significant impact on mutation rate or type. Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.
Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-05-2021
DOI: 10.1200/JCO.20.03296
Abstract: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,542 patients with complete information on potentially relevant variables. The results were validated in an independent data set. Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided ( www.eortc.org/IGCCCG-Update ). The IGCCCG Update model improves in idual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.
Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 02-2021
DOI: 10.1158/2326-6066.CIR-20-0401
Abstract: Combined inhibition of BRAF, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a BRAFV600 mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic BrafV600ECdkn2a−/−Pten−/− melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA sequencing analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted proinflammatory macrophages and cross-priming CD103+ dendritic cells, the absence of which correlated with poor overall survival and clinical responses to ICB in patients with melanoma. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses ex vivo. While combined BRAF, MEK, and CDK4/6 inhibition demonstrates favorable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact antitumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRAF, MEK, and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma.
Desmoglein 2 promotes vasculogenic mimicry in melanoma and is associated with poor clinical outcome
Publisher: Impact Journals, LLC
Date: 22-06-2016
Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling
Publisher: Impact Journals, LLC
Date: 06-07-2016
Long term, continuous exposure to panobinostat induces terminal differentiation and long term survival in the TH‐MYCN neuroblastoma mouse model
Publisher: Wiley
Date: 10-03-2016
DOI: 10.1002/IJC.30056
Abstract: Neuroblastoma is the most common extra-cranial malignancy in childhood and accounts for ∼15% of childhood cancer deaths. Amplification of MYCN in neuroblastoma is associated with aggressive disease and predicts for poor prognosis. Novel therapeutic approaches are therefore essential to improving patient outcomes in this setting. The histone deacetylases are known to interact with N-Myc and regulate numerous cellular processes via epigenetic modulation, including differentiation. In this study, we used the TH-MYCN mouse model of neuroblastoma to investigate the antitumor activity of the pan-HDAC inhibitor, panobinostat. In particular we sought to explore the impact of long term, continuous panobinostat exposure on the epigenetically driven differentiation process. Continuous treatment of tumor bearing TH-MYCN transgenic mice with panobinostat for nine weeks led to a significant improvement in survival as compared with mice treated with panobinostat for a three-week period. Panobinostat induced rapid tumor regression with no regrowth observed following a nine-week treatment period. Initial tumor response was associated with apoptosis mediated via upregulation of BMF and BIM. The process of terminal differentiation of neuroblastoma into benign ganglioneuroma, with a characteristic increase in S100 expression and reduction of N-Myc expression, occurred following prolonged exposure to the drug. RNA-sequencing analysis of tumors from treated animals confirmed significant upregulation of gene pathways associated with apoptosis and differentiation. Together our data demonstrate the potential of panobinostat as a novel therapeutic strategy for high-risk neuroblastoma patients.
Dysregulation of the basal RNA polymerase transcription apparatus in cancer
Publisher: Springer Science and Business Media LLC
Date: 24-04-2013
DOI: 10.1038/NRC3496
Abstract: Mutations that directly affect transcription by RNA polymerases rank among the most central mediators of malignant transformation, but the frequency of new anticancer drugs that selectively target defective transcription apparatus entering the clinic has been limited. This is because targeting the large protein-protein and protein-DNA interfaces that control both generic and selective aspects of RNA polymerase transcription has proved extremely difficult. However, recent technological advances have led to a 'quantum leap' in our comprehension of the structure and function of the core RNA polymerase components, how they are dysregulated in a broad range of cancers and how they may be targeted for 'transcription therapy'.
Phenotype switching in melanoma: implications for progression and therapy.
Publisher: Frontiers Media SA
Date: 13-02-2015
The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-08-2015
DOI: 10.1126/SCISIGNAL.AAB1111
Abstract: The transcriptional regulator c-JUN is a key mediator of the metastatic potential and drug resistance in melanoma.
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
Publisher: Massachusetts Medical Society
Date: 30-06-2011
Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study
Publisher: Elsevier BV
Date: 05-2017
Abstract: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58 P < 0.0001] and overall survival (HR, 0.70 P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study. Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations. Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247 vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation. These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care. NCT01689519.
Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-05-2021
DOI: 10.1200/JCO.20.03292
Abstract: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium. Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients. Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH. PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.
Long-term outcome in BRAF(V600E) melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression.
Publisher: Elsevier BV
Date: 07-2015
Checkpoint inhibitors in melanoma and early phase development in solid tumors: what’s the future?
Publisher: Springer Science and Business Media LLC
Date: 08-08-2017
5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation–Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study
Publisher: American Association for Cancer Research (AACR)
Date: 22-06-2021
DOI: 10.1158/1078-0432.CCR-21-0809
Abstract: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation–positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized. Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1–21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily). 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3–28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0–19.8) with placebo plus vemurafenib 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5–14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6–7.5) with placebo plus vemurafenib 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports. Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation–positive advanced melanoma.
Randomized phase II study evaluating veliparib (ABT-888) with temozolomide in patients with metastatic melanoma.
Publisher: Elsevier BV
Date: 10-2015
Abstract: Veliparib (ABT-888) is a potent, orally bioavailable, small-molecule inhibitor of the DNA repair enzymes poly ADP-ribose polymerase-1 and -2. Veliparib enhances the efficacy of temozolomide (TMZ) and other cytotoxic agents in preclinical tumor models. In this multicenter, double-blind trial, adults with unresectable stage III or IV metastatic melanoma were randomized 1:1:1 to TMZ plus veliparib 20 or 40 mg, or placebo twice daily. Efficacy end points included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Patients (N = 346) were randomized between February 2009 and January 2010. Median [95% confidence interval (CI)] PFS was 3.7 (3.0-5.5), 3.6 (1.9-4.1), and 2 (1.9-3.7) months in the 20-mg, 40-mg, and placebo arms, respectively. Median (95% CI) OS was 10.8 (9.0-13.1), 13.6 (11.4-15.9), and 12.9 (9.8-14.3) months, respectively ORR was 10.3%, 8.7%, and 7.0%. Exploratory analyses showed patients with low ERCC1 expression had longer PFS when TMZ was combined with veliparib. Toxicities were as expected for TMZ. The frequencies of thrombocytopenia, neutropenia, and leukopenia were significantly increased in the veliparib groups. Grade 3 or 4 adverse events, mainly hematologic toxicities, were seen in 55%, 63%, and 41% of patients in the 20-mg, 40-mg, and placebo arms, respectively. Median PFS with 20 and 40 mg veliparib almost doubled numerically compared with placebo, but the improvements did not reach statistical significance. OS was not increased with veliparib. Toxicities were similar to TMZ monotherapy, but with increased frequency.
Expanded access programmes: patient interests versus clinical trial integrity
Publisher: Elsevier BV
Date: 2015
Supplementary Tables from γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543536
Abstract: Supplementary Tables
Targeting the nucleolus for cancer-specific activation of p53
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.DRUDIS.2013.08.012
Abstract: The tumor suppressor protein p53 plays a crucial part in the cellular defense against malignancies. DNA-damaging chemotherapeutics rely on the activation of p53 for their anticancer activity at the expense of genotoxicity. Nongenotoxic approaches for p53 activation have been extensively investigated validating p53 as a therapeutic target. However, their development has been h ered by low efficacy and a narrow therapeutic window. An alternate nongenotoxic approach for cancer-specific activation of wild-type p53 has been recently identified. It relies on the activation of a cellular checkpoint mechanism termed 'nucleolar stress', which can be triggered by acute inhibition of rRNA biogenesis. CX5461, the first selective inhibitor of rRNA biogenesis, and thus a potent activator of nucleolar stress, is poised to enter clinical development.
Cell Cycle Regulation and Melanoma
Publisher: Springer Science and Business Media LLC
Date: 22-04-2016
DOI: 10.1007/S11912-016-0524-Y
Abstract: Dysregulation of cell cycle control is a hallmark of melanomagenesis. Agents targeting the G1-S and G2-M checkpoints, as well as direct anti-mitotic agents, have all shown promising preclinical activity in melanoma. However, in vivo, standalone single agents targeting cell cycle regulation have only demonstrated modest efficacy in unselected patients. The advent of specific CDK 4/6 inhibitors targeting the G1-S transition, with an improved therapeutic index, is a significant step forward. Potential synergy exists with the combination of CDK4/6 inhibitors with existing therapies targeting the MAPK pathway, particularly in subsets of metastatic melanomas such as NRAS and BRAF mutants. This reviews summaries of the latest developments in both preclinical and clinical data with cell cycle-targeted therapies in melanoma.
High-resolution MRI demonstrates that more than 90% of small intracranial melanoma metastases develop in close relationship to the leptomeninges
Publisher: Oxford University Press (OUP)
Date: 09-09-2019
Abstract: Despite classic teaching that intracranial metastases typically arise at the gray–white matter junction, small intracranial melanoma metastases (IMM) are frequently observed at the interface between the cortex and leptomeninges (ie, “corticomeningeal interface”), suggesting possible leptomeningeal origin. MRI brain examinations of melanoma patients treated at a specialist oncology center from July 2015 to June 2017 were retrospectively reviewed. The MRI examination on which IMM were first visible was identified, utilizing 1 mm volumetric postcontrast imaging prior to local therapy. In idual metastases (up to 10 per patient) were assessed for the presence of leptomeningeal contact, as well as their number, size, and morphology. Lesions ≥10 mm in long axis were excluded, in order to examine early metastatic disease. Seventy-five patients had evidence of IMM. Fifteen patients had only lesion(s) measuring ≥10 mm at diagnosis, leaving 60 patients. One hundred ninety-two in idual metastases were examined (median 2 per patient interquartile range, 1–4), 174 (91%) demonstrating leptomeningeal contact. A nodular morphology was observed in 154 of 192 (82%), 32 (17%) were ovoid but elongated along the cortex, and 6 (3%) were linear. Only 3 patients (5%) also exhibited a “classic” linear leptomeningeal disease appearance. Most IMM measuring between 2 and 9 mm in diameter are corticomeningeal nodules. These data raise the hypothesis that deeper parenchymal extension of IMM occurs secondarily. If the leptomeninges provide a preferential site for establishment of IMM, further investigation of the underlying biology of this phenomenon may provide opportunities for novel therapeutic strategies for patients with IMM. 1. Most small IMM develop at the corticomeningeal interface, rather than the gray‒white junction. 2. This suggests that the pia mater provides a preferential site for establishment of IMM. 3. Deeper brain parenchymal extension may occur secondarily.
The promise of PET in clinical management and as a sensitive test for drug cytotoxicity in sarcomas
Publisher: Informa UK Limited
Date: 2008
Abstract: Positron emission tomography (PET) is a noninvasive functional imaging technique that allows assessment of key biological processes important in cancer development and progression. It provides information complementary to conventional anatomic imaging, demonstrating utility in a range of cancer settings from diagnosis, biopsy guidance, tumor stratification and prognostication, and staging and surveillance of disease recurrence. Its ability to evaluate vital processes in tumor biology also makes it a potentially valuable and sensitive tool for assessing therapeutic response. The development of novel PET tracers and improvements in technology will only continue to augment the potential of PET and enhance its attractiveness as an instrument to facilitate drug development. This article will discuss the above issues, using the setting of sarcomas as an ex le.
CDK4 inhibitors an emerging strategy for the treatment of melanoma
Publisher: Future Medicine Ltd
Date: 08-2015
DOI: 10.2217/MMT.15.14
Abstract: Research into the cyclin-dependent kinases and their inhibitors is finally coming into the forefront of clinical research in cancer. Targeted therapies such as BRAF inhibitors have led the way in improving treatment outcomes in advanced melanoma. Based on detailed genomic knowledge of melanoma it is now time to extend targeted therapies beyond BRAF to fulfill the vision of precision medicine. The p16 INK4A -cyclin D-CDK4/6-retinoblastoma protein pathway (RB pathway) is dysregulated in more than 90% of melanomas and interacts biochemically and genetically with the RAS/RAF/MEK/ERK pathway. Recognizing and understanding these processes that drive melanomagenesis is essential to rationally develop new therapies. This paper reviews the mechanisms, background and progress of small molecule CDK4 inhibitors in the management of melanoma.
Clustered somatic mutations are frequent in transcription factor binding motifs within proximal promoter regions in melanoma and other cutaneous malignancies.
Publisher: Impact Journals, LLC
Date: 07-09-2016
Targeted-capture massively-parallel sequencing enables robust detection of clinically informative mutations from formalin-fixed tumours.
Publisher: Springer Science and Business Media LLC
Date: 13-12-2013
DOI: 10.1038/SREP03494
Targeting NRAS in Melanoma
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2012
Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 15-03-2009
DOI: 10.1158/1078-0432.CCR-08-2484
Abstract: Purpose: NY-ESO-1 is a highly immunogenic antigen expressed in a variety of malignancies, making it an excellent target for cancer vaccination. We recently developed a vaccine consisting of full-length recombinant NY-ESO-1 protein formulated with ISCOMATRIX adjuvant, which generated strong humoral and T-cell–mediated immune responses and seemed to reduce the risk of disease relapse in patients with fully resected melanoma. This study examines the clinical and immunologic efficacy of the same vaccine in patients with advanced metastatic melanoma. Experimental Design: Delayed-type hypersensitivity responses, circulating NY-ESO-1–specific CD4+ and CD8+ T cells, and proportions of regulatory T cells (Treg) were assessed in patients. Results: In contrast to patients with minimal residual disease, advanced melanoma patients showed no clinical responses to vaccination. Although strong antibody responses were mounted, the generation of delayed-type hypersensitivity responses was significantly impaired. The proportion of patients with circulating NY-ESO-1–specific CD4+ T cells was also reduced, and although many patients had CD8+ T cells specific to a broad range of NY-ESO-1 epitopes, the majority of these responses were preexisting. Tregs were enumerated in the blood by flow cytometric detection of cells with a CD4+CD25+FoxP3+ and CD4+CD25+CD127− phenotype. Patients with advanced melanoma had a significantly higher proportion of circulating Treg compared with those with minimal residual disease. Conclusions: Our results point to a tumor-induced systemic immune suppression, showing a clear association between the stage of melanoma progression, the number of Treg in the blood, and the clinical and immunologic efficacy of the NY-ESO-1 ISCOMATRIX cancer vaccine.
Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study
Publisher: Elsevier BV
Date: 03-2017
Abstract: Vemurafenib has shown activity in patients with BRAFV600 mutated melanoma with brain metastases (BM). This phase 2 study evaluated vemurafenib in patients with/without prior treatment for BM. Patients with BRAFV600 mutated melanoma with BM were enrolled into cohort 1 (previously untreated BM) and cohort 2 (previously treated BM) and received vemurafenib (960 mg BID) until disease progression (PD) or intolerance. Primary endpoint was best overall response rate (BORR) in the brain in cohort 1 that was evaluated using modified RECIST 1.1 criteria using lesions ≥0.5 cm to assess response. 146 patients were treated (cohort 1 n = 90 cohort 2 n = 56), 62% of whom were male. Median (range) time since diagnosis of BM: 1.0 (0-9) month in cohort 1 and 4.2 (1-68) months in cohort 2. Median duration of treatment was 4.1 months (range 0.3-34.5) in cohort 1 and 4.1 months (range 0.2-27.6) in cohort 2. Intracranial BORR in cohort 1 by an independent review committee (IRC) was 18% (2 CRs, 14 PRs). Extracranial BORR by IRC was 33% in cohort 1 and 23% in cohort 2. Median PFS (brain only, investigator-assessed) was 3.7 months (range 0.03-33.4 IQR 1.9-5.6) in cohort 1 and 4.0 months (range 0.3-27.4 IQR 2.2-7.4) in cohort 2. Median OS was 8.9 months (range 0.6-34.5 IQR 4.9-17.0) in cohort 1 and 9.6 months (range 0.7-34.3 IQR 4.5-18.4) in cohort 2. Adverse events (AEs) were similar in type, grade and frequency to other studies of single-agent vemurafenib. Grade 3/4 AEs occurred in 59 (66%) patients in cohort 1 and 36 (64%) in cohort 2. Overall, 84% of patients died during the study (86% in cohort 1 and 80% in cohort 2), mainly due to disease progression. The study demonstrates clinically meaningful response rates of melanoma BM to vemurafenib, which was well tolerated and without significant CNS toxicity.
Supplementary Figures from γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543539
Abstract: Supplementary Figures
ATRA and the specific RARα agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells
Publisher: Springer Science and Business Media LLC
Date: 11-12-2012
DOI: 10.1038/LEU.2012.362
Abstract: All-trans retinoic acid (ATRA) is used successfully in the treatment of acute promyelocytic leukemia (APL). ATRA enhances hematopoietic stem cell self-renewal through retinoic acid receptor (RAR)γ activation while promoting differentiation of committed myeloid progenitors through RARα activation. Its lack of success in the treatment of non-APL acute myeloid leukemia (AML) may be related to ATRA's non-selectivity for the RARα and RARγ isotypes, and specific RARα activation may be more beneficial in promoting myeloid differentiation. To investigate this hypothesis, the effects of ATRA and the specific RARα agonist NRX195183 was assessed in AML1-ETO (AE)-expressing murine bone marrow (BM) progenitors. ATRA potentiated the in vitro clonogenicity of these cells while NRX195183 had the opposite effect. Morphological and flow cytometric analysis confirmed a predominantly immature myeloid population in the ATRA-treated AE cells while the NRX195183-treated cells demonstrated an increase in the mature myeloid population. Similarly, NRX195183 treatment promoted myeloid differentiation in an AE9a in vivo murine model. In the ATRA-treated AE cells, gene expression analyses revealed functional networks involving SERPINE1 and bone morphogenetic protein 2 AKT phosphorylation was upregulated. Collectively, these findings confirm the contrasting roles of specific RARα and RARγ activation in the clonogenicity and differentiation of AE cells with potential significant implications in the treatment of non-APL AML using a specific RARα agonist.
Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.
Publisher: Elsevier BV
Date: 10-2006
Impact of MET expression on outcome in BRAFV600E/Kadvanced melanoma
Publisher: Wiley
Date: 26-06-2013
DOI: 10.1111/HIS.12169
Abstract: Preclinical data suggest that signalling through the HGF-MET pathway may confer resistance to BRAF inhibition in BRAF(V600E/K) melanoma. Therefore, blockade of HGF-MET signalling might be a valid therapeutic strategy, in combination with BRAF inhibition, in BRAF(V600E/K) melanoma. The aim of this study was to investigate the clinical relevance of these observations by evaluating the survival impact of MET expression in patients with BRAF(V600E/K) advanced melanoma treated with vemurafenib. Formalin-fixed tissue blocks were obtained of tumours from patients enrolled in the BRIM2 (n = 59) and BRIM3 (n = 150) trials of vemurafenib in advanced BRAF(V600E/K) melanoma. Immunohistochemistry for MET (SP44 rabbit monoclonal antibody) was performed with a highly validated assay and clinically validated scoring system. Pretreatment MET expression was frequent at the ≥1 + cutoff (BRIM3, 31% BRIM2, 49%), but relatively infrequent at the ≥2 + cutoff (BRIM3, 9% BRIM2, 19%). Retrospective subset analyses showed that, irrespective of the cutoff used or the treatment arm, MET expression did not show prognostic significance, in terms of objective response rate, progression-free survival, or overall survival. MET is expressed in a proportion of BRAF(V600E/K) advanced melanomas. Further analyses on appropriately powered subsets are needed to determine the prognostic and predictive significance of MET in vemurafenib-treated melanoma.
Supplementary Data from γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543542
Abstract: RNA-seq and scRNA-seq count data and TCR contigs
Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population
Publisher: American Society of Hematology
Date: 25-05-2017
DOI: 10.1182/BLOOD-2016-05-718171
Abstract: Inhibition of RNA Pol I by CX-5461 treats aggressive AML and outperforms standard chemotherapy regimens. CX-5461 induces p53-dependent apoptosis, p53-independent cell-cycle defects and differentiation, and reduces LICs.
Ubiquitous expression of the Pik3ca H1047R mutation promotes hypoglycemia, hypoinsulinemia, and organomegaly
Publisher: Wiley
Date: 30-12-2014
DOI: 10.1096/FJ.14-262782
Abstract: Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common mutations found in human cancer and have also recently been implicated in a range of overgrowth syndromes in humans. We have used a novel inducible "exon-switch" approach to knock in the constitutively active Pik3ca(H1047R) mutation into the endogenous Pik3ca gene of the mouse. Ubiquitous expression of the Pik3ca(H1047R) mutation throughout the body resulted in a dramatic increase in body weight within 3 weeks of induction (mutant 150 ± 5% wild-type 117 ± 3%, mean ± sem), which was associated with increased organ size rather than adiposity. Severe metabolic effects, including a reduction in blood glucose levels to 59 ± 4% of baseline (11 days postinduction) and undetectable insulin levels, were also observed. Pik3ca(H1047R) mutant mice died earlier (median survival 46.5 d post-mutation induction) than wild-type control mice (100% survival > 250 days). Although deletion of Akt2 increased median survival by 44%, neither organ overgrowth, nor hypoglycemia were rescued, indicating that both the growth and metabolic functions of constitutive PI3K activity can be Akt2 independent. This mouse model demonstrates the critical role of PI3K in the regulation of both organ size and glucose metabolism at the whole animal level.
Combination anti-CTLA-4 and Anti-RANKL in metastatic melanoma
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-04-2014
BRAF/NRAS wild-type melanomas have a high mutation load correlating with histologic and molecular signatures of UV damage.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2013
DOI: 10.1158/1078-0432.CCR-13-0398
Abstract: Purpose: The mutation load in melanoma is generally high compared with other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinicopathologic features. Experimental Design: DNA was extracted from 34 fresh-frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was conducted and mutation rates were correlated with age, sex, tumor site, and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation, and BRAF/NRAS mutational status were investigated. Results: The average mutation rate was 12 per megabase, similar to published results in metastases. The average mutation rate in severely sun damaged (SSD) skin was 21 per Mb compared with 3.8 per Mb in non-SSD skin (P = 0.001). BRAF/NRAS wild-type (WT) tumors had a higher average mutation rate compared with BRAF/NRAS–mutant tumors (27 vs. 5.6 mutations per Mb P = 0.0001). Tandem CC& TT/GG& AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin (P = 0.0008) and in BRAF/NRAS WT tumors (P = 0.0007). Targetable and potentially targetable mutations in WT tumors, including NF1, KIT, and NOTCH1, were spread over various signaling pathways. Conclusion: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF- and NRAS-mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients. Clin Cancer Res 19(17) 4589–98. ©2013 AACR.
Supplementary Data from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486697.V1
Abstract: Supplementary Data from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 15-06-2007
DOI: 10.1158/1078-0432.CCR-07-0410
Abstract: Purpose: Human interleukin-21 (IL-21) is a pleiotropic class I cytokine that activates CD8+ T cells and natural killer cells. We report a phase 1 study of recombinant human IL-21 in patients with surgically incurable metastatic melanoma. The primary objective was to investigate safety and tolerability by determining dose-limiting toxicity (DLT). The secondary objectives were to identify a dose response for various biomarkers in the peripheral blood, estimate the minimum biologically effective dose, determine the pharmacokinetics of IL-21, determine if anti-IL-21 antibodies were induced during therapy, and measure effects on tumor size according to Response Evaluation Criteria in Solid Tumors. Experimental Design: Open-label, two-arm, dose escalation trial of IL-21 administered by i.v. bolus injection at dose levels from 1 to 100 μg/kg using two parallel treatment regimens: thrice weekly for 6 weeks (3/wk) or three cycles of daily dosing for 5 days followed by 9 days of rest (5+9). Results: Twenty-nine patients entered the study. IL-21 was generally well tolerated and no DLTs were observed at the 1, 3, and 10 μg/kg dose levels. In the 3/wk regimen, DLTs were increased in alanine aminotransferase, neutropenia, and lightheadedness with fever and rigors. DLTs in the 5+9 regimen were increased in aspartate aminotransferase and alanine aminotransferase, neutropenia, fatigue, and thrombocytopenia. The maximum tolerated dose was declared to be 30 μg/kg for both regimens. Effects on biomarkers were observed at all dose levels, including increased levels of soluble CD25 and up-regulation of perforin and granzyme B mRNA in CD8+ cells. One partial tumor response observed after treatment with IL-21 for 2 × 6 weeks (3/wk) became complete 3 months later. Conclusions: IL-21 is biologically active at all dose levels administered and is generally well tolerated, and phase 2 studies have commenced using 30 μg/kg in the 5+9 regimen.
Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases
Publisher: Springer Science and Business Media LLC
Date: 10-10-2017
DOI: 10.1245/S10434-017-6072-3
Abstract: This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV melanoma. After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS) secondary endpoints were disease-free survival (DFS), and immune response measured by skin test (ClinicalTrials.gov identifier: NCT00052156). Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18 p = 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group (HR 1.053 p = 0.696). Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group (HR 0.882 p = 0.260). Positive DTH skin testing correlated with increased survival. In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG lacebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.
Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma
Publisher: American Association for Cancer Research (AACR)
Date: 2016
DOI: 10.1158/2159-8290.CD-14-0673
Abstract: Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I–mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K–AKT–mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYC-driven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma–bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. Significance: Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma–bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov 6(1) 59–70. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 1
Melanoma: the intersection of molecular targeted therapy and immune checkpoint inhibition.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.COI.2015.12.006
Abstract: Melanoma is at the forefront of development of systemic therapeutics with both molecular targeted therapies and immune checkpoint inhibitors as cornerstones of treatment. Although responses to molecularly targeted therapy is largely from blockade of oncogenic pathways, evidence is emerging of the immunomodulatory effects from BRAF inhibition. Additionally programmed-death-1 (PD-1) inhibitors have revolutionized the treatment of melanoma and are set to pave future improvements in other solid tumors. Combinations of PD-1 inhibitors with novel immune checkpoints or with molecularly targeted therapies are under investigation and may improve on the considerable progress made.
Data from γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2018
DOI: 10.1158/2326-6066.C.6550308.V1
Abstract: Abstract Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4 sup + /sup or CD8 sup + /sup T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates ( % DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2 sup − /sup γδ T cells. In the context of γδ T–cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T–cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti–PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T–cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions. i See related Spotlight on p. 600 /i /
PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer.
Publisher: Proceedings of the National Academy of Sciences
Date: 17-05-2010
Abstract: PIK3CA mutations are reported to be present in approximately 25% of breast cancer (BC), particularly the estrogen receptor–positive (ER+) and HER2-overexpressing (HER2+) subtypes, making them one of the most common genetic aberrations in BC. In experimental models, these mutations have been shown to activate AKT and induce oncogenic transformation, and hence these lesions have been hypothesized to render tumors highly sensitive to therapeutic PI3K/mTOR inhibition. By analyzing gene expression and protein data from nearly 1,800 human BCs, we report that a PIK3CA mutation–associated gene signature ( PIK3CA -GS) derived from exon 20 (kinase domain) mutations was able to predict PIK3CA mutation status in two independent datasets, strongly suggesting a characteristic set of gene expression–induced changes. However, in ER+/HER2− BC despite pathway activation, PIK3CA mutations were associated with a phenotype of relatively low mTORC1 signaling and a good prognosis with tamoxifen monotherapy. The relationship between clinical outcome and the PIK3CA -GS was also assessed. Although the PIK3CA -GS was not associated with prognosis in ER− and HER2+ BC, it could identify better clinical outcomes in ER+/HER2− disease. In ER+ BC cell lines, PIK3CA mutations were also associated with sensitivity to tamoxifen. These findings could have important implications for the treatment of PIK3CA -mutant BCs and the development of PI3K/mTOR inhibitors.
Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.EJCA.2013.08.007
Abstract: Ovarian cancer is the major cause of death from gynaecological malignancy with a 5year survival of only ∼30% due to resistance to platinum and paclitaxel-based first line therapy. Dysregulation of the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) and RAS/extracellular signal-regulated kinase (ERK) pathways is common in ovarian cancer, providing potential new targets for 2nd line therapy. We determined the inhibition of proliferation of an extensive panel of ovarian cancer cell lines, encompassing all the major histotypes, by the dual PI3K/mTOR inhibitor PF-04691502 and a MEK inhibitor, PD-0325901. In addition, we analysed global gene expression, mutation status of key PI3K/mTOR and RAS/ERK pathway members and pathway activation to identify predictors of drug response. PF-04691502 inhibits proliferation of the majority of cell lines with potencies that correlate with the extent of pathway inhibition. Resistant cell lines were characterised by activation of the RAS/ERK pathway as indicated by differential gene expression profiles and pathway activity analysis. PD-0325901 suppressed growth of a subset of cell lines that were characterised by high basal RAS/ERK signalling. Strikingly, using PF-04691502 and PD-0325901 in combination resulted in synergistic growth inhibition in 5/6 of PF-04691502 resistant cell lines and two cell lines resistant to both single agents showed robust synergistic growth arrest. Xenograft studies confirm the utility of combination therapy to synergistically inhibit tumour growth of PF-04691502-resistant tumours in vivo. These studies identify dual targeted inhibitors of PI3K/mTOR in combination with inhibitors of RAS/ERK signalling as a potentially effective new approach to treating ovarian cancer.
Cyclin-Dependent Kinase 2 Functions in Normal DNA Repair and Is a Therapeutic Target in BRCA1-Deficient Cancers
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2006
DOI: 10.1158/0008-5472.CAN-05-3945
Abstract: Abnormal regulation of progression from G1 to S phase of the cell cycle by altered activity of cyclin-dependent kinases (CDKs) is a hallmark of cancer. However, inhibition of CDKs, particularly CDK2, has not shown selective activity against most cancer cells because the kinase seems to be redundant in control of cell cycle progression. Here, we show a novel role in the DNA damage response and application of CDK inhibitors in checkpoint-deficient cells. CDK2−/− mouse fibroblasts and small interfering RNA–mediated or small-molecule–mediated CDK2 inhibition in MCF7 or U2OS cells lead to delayed damage signaling through Chk1, p53, and Rad51. This coincided with reduced DNA repair using the single-cell comet assay and defects observed in both homologous recombination and nonhomologous end-joining in cell-based assays. Furthermore, tumor cells lacking cancer predisposition genes BRCA1 or ATM are 2- to 4-fold more sensitive to CDK inhibitors. These data suggest that inhibitors of CDK2 can be applied to selectively enhance responses of cancer cells to DNA-damaging agents, such as cytotoxic chemotherapy and radiotherapy. Moreover, inhibitors of CDKs may be useful therapeutics in cancers with defects in DNA repair, such as mutations in the familial breast cancer gene BRCA1. (Cancer Res 2006 66(16): 8219-26)
First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 13-06-2022
DOI: 10.1158/1078-0432.CCR-21-4020
Abstract: OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG1 monoclonal anti-OX40 antibody. Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2–1,200 mg n = 34) was followed by expansion cohorts at 300 mg (n = 138) for patients with melanoma, renal cell carcinoma, non–small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer. MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE) 56% of AEs, mostly grade 1–2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease. Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists.
Ocular toxicity in BRAF mutant cutaneous melanoma patients treated with vemurafenib.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.AJO.2014.07.003
Abstract: To determine the frequency of ocular adverse effects associated with vemurafenib (PLX4032) treatment for metastatic cutaneous melanoma. Retrospective review of the clinical study reports from the clinical pharmacology, phase 1, phase 2, and phase 3 trials of vemurafenib. The vemurafenib clinical trials were a multicenter series involving adult patients with histologically confirmed, BRAF(V600) mutation-positive, unresectable, stage IIIC or IV melanoma. A total of 855 patients were enrolled in the trials: 568 patients were treated with vemurafenib and 287 patients were treated with dacarbazine. Among the 568 patients treated with vemurafenib, ocular adverse effects developed in 22% (95% confidence interval [CI], 18.5-25.6). The most common ocular diagnosis was uveitis (4.0% 95% CI, 2.6-6.0), followed by conjunctivitis (2.8% 95% CI, 1.6-4.5) and dry eyes (2.0% 95% CI, 1.1-3.7). All were successfully managed while vemurafenib therapy was continued. Ocular adverse events and symptoms may be seen in more than one-fifth of patients being treated with vemurafenib. However, vemurafenib can be continued while the ocular symptoms are being managed. The pathogenesis of ocular symptoms in this patient population is unclear additional studies are necessary.
Sentinel Lymph Node Biopsy in T4 Melanoma: An Important Risk-Stratification Tool.
Publisher: Springer Science and Business Media LLC
Date: 15-10-2016
DOI: 10.1245/S10434-015-4894-4
Abstract: Sentinel lymph node biopsy (SLNB) is a sensitive test for detecting subclinical nodal metastatic disease in patients with melanoma without evidence of lymph node involvement. The prognostic significance of SLN positivity in patients with melanoma >4 mm thick (T4) is unclear. The survival curves in the current AJCC staging system suggest that the status of the SLN is not predictive of outcome for patients with T4 melanoma. Patients with primary T4 melanoma without clinical nodal involvement who underwent SLNB between 2002 and 2012 at Peter MacCallum Cancer Centre were included in the analysis with chart review performed to collect clinical, pathological, and outcome data. A meta-analysis was performed including similar studies of SLNB in T4 melanoma, which reported overall survival (OS) data. Of 217 patients who underwent SLNB, 78 patients had a positive SLN (36 %). The 5-year OS for SLNB negative and positive patients was 68 and 45 %, respectively [hazard ratio (HR) 2.82 95 % CI 1.76-4.51 P = .001]. On multivariate analysis, the only predictors of OS were the status of the SLN (HR 2.88 95 % CI 1.75–4.73) and the presence of satellitosis (HR 2.59 95 % CI 1.30-5.76). The meta-analysis identified 10 studies that met the inclusion criteria. All reported similar findings, demonstrating a significant difference in OS according to sentinel lymph node status the pooled analysis of 2104 patients demonstrated an overall HR for OS according to SLNB status of 2.3 (95 % CI 1.95-2.71). SLNB provides important prognostic information for patients with T4 melanoma. This information is important when stratifying patients for clinical trials.
Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study.
Publisher: Elsevier BV
Date: 08-2014
CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory
Publisher: American Association for Cancer Research (AACR)
Date: 14-05-2021
DOI: 10.1158/2159-8290.CD-20-1554
Abstract: Immunologic memory is critical for sustained antitumor immunity. Our discovery that CDK4/6 inhibitors drive T-cell memory fate commitment sheds new light on their clinical activity, which is essential for the design of clinical trial protocols incorporating these agents, particularly in combination with immunotherapy, for the treatment of cancer. This article is highlighted in the In This Issue feature, p. 2355
Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2013
Abstract: BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma. This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily. In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD) the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%) the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed. Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor–naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor–naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486667
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2014
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486676
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486673
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Complete Longitudinal Analyses of the Randomized, Placebo-Controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor following Imatinib Failure
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2012
DOI: 10.1158/1078-0432.CCR-11-3005
Abstract: Purpose: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure to assess correlative angiogenesis biomarkers with patient outcomes. Experimental Design: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. Results: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks HR, 0.876 P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262–1.134 P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. Conclusions: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events. Clin Cancer Res 18(11) 3170–9. ©2012 AACR.
The granulocyte-colony stimulating factor receptor (G-CSFR) interacts with retinoic acid receptors (RARs) in the regulation of myeloid differentiation
Publisher: Oxford University Press (OUP)
Date: 02-2013
DOI: 10.1189/JLB.1211609
Abstract: Residual granulopoiesis persists in mice lacking both G-CSFR and RARα, or RARγ G-CSFR is required for granulopoietic expansion seen with loss of RARγ. The key roles of RARs and G-CSFR in the regulation of granulopoiesis have been well-documented. In this study, we sought to investigate the interaction between G-CSFR and RARs in myeloid differentiation of adult mice through conditional deletion of RARα or RARγ on a G-CSFR−/− background and by pharmacological intervention of WT and G-CSFR−/− mice with a pan-RAR inverse agonist, NRX194310. Our findings show that residual granulopoiesis still persists in mice doubly null for G-CSFR and RARα or RARγ, confirming that RARs and G-CSFR are dispensable in maintaining residual granulopoiesis. Moreover, an increase in mature myeloid cells was seen in the conditional RARγΔ/Δ mice and WT mice treated with NRX194310, likely mediated through increased G-CSF production. However, with the loss of G-CSFR, this expansion in granulopoiesis was attenuated, supporting the hypothesis that G-CSFR signaling interacts with RARs in the regulation of myeloid differentiation.
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486670
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486682.V1
Abstract: Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Supplementary Tables from γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543536.V1
Abstract: Supplementary Tables
Imatinib as effective therapy for dermatofibrosarcoma protuberans: proof of concept of the autocrine hypothesis for cancer
Publisher: Future Medicine Ltd
Date: 04-2008
Abstract: Cancer literature has consistently described autocrine loops involving growth factors to be important mechanisms for cellular transformation and proliferation in preclinical cancer models. Finally, convincing clinical data exist to implicate autocrine loops as central to the pathogenesis of a malignant condition, largely as a result of the recent development of inhibitors of protein tyrosine kinases important in cell signaling and growth. Although a rare condition, the study of patients with dermatofibrosarcoma protuberans (DFSP) is enriched by data demonstrating strong scientific rationale for its pathogenesis and susceptibility to molecular-based therapies. DFSP is a low-grade sarcoma that responds to treatment with imatinib, an inhibitor of the PDGF receptor tyrosine kinase. This treatment response illustrates the importance of autocrine aracrine loops involving PDGF and its receptor as the key molecular target in DFSP. New insight into this fundamental biological mechanism sets the scene for the further development of molecular-targeted therapeutic options for cancer.
Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study
Publisher: Springer Science and Business Media LLC
Date: 24-06-2017
DOI: 10.1186/S12967-017-1246-0
Abstract: Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF V600 -mutated melanoma treated in the Phase III coBRIM study. In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms. Eighty-six serous retinopathy events were reported in 70 patients (79 events in 63 cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during cobimetinib and vemurafenib treatment median time to onset was 1.0 month. Most events were managed by observation and continuation of cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014). Cobimetinib treatment was associated with serous retinopathy in patients with BRAF V600 -mutated melanoma. Retinopathy was generally asymptomatic or mild. Periodic ophthalmologic evaluations at regular intervals and at the manifestation of any visual disturbance are recommended to facilitate early detection and resolution of serous retinopathy while patients are taking cobimetinib. Trial Registration Clinicaltrials.gov (NCT01689519). First received: September 18, 2012
Supplementary Figures from Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543851.V1
Abstract: Supplementary Figures S1-S5
Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma
Publisher: BMJ
Date: 04-2020
Abstract: To compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence. Participants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity. The ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4 + and CD8 + responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1) + /Human Leukocyte Antigen (HLA) class I + double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants. The vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.
Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 19-09-2017
DOI: 10.1038/S41467-017-00728-9
Abstract: The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo. This effect is dependent upon increased downstream p38/JNK pathway activation. Taken together, our data suggest that although Ras/MAPK pathway inhibition can increase tumor immunogenicity, the negative impact on T-cell activity is functionally important. This undesirable impact is effectively prevented by combination with T-cell immune agonist immunotherapies resulting in superior therapeutic efficacy.
Data from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532370.V1
Abstract: AbstractPurpose: OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG sub /sub monoclonal anti-OX40 antibody. Patients and Methods: Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2–1,200 mg i n /i = 34) was followed by expansion cohorts at 300 mg ( i n /i = 138) for patients with melanoma, renal cell carcinoma, non–small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer. Results: MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE) 56% of AEs, mostly grade 1–2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease. Conclusions: Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists. /
Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib
Publisher: Elsevier BV
Date: 07-2012
Abstract: This phase III open-label trial investigated the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors following prior imatinib and sunitinib failure. Patients were randomized 2:1 to nilotinib 400 mg b.i.d. or best supportive care (BSC BSC without tyrosine kinase inhibitor, BSC+imatinib, or BSC+sunitinib). Primary efficacy end point was progression-free survival (PFS) based on blinded central radiology review (CRR). Patients progressing on BSC could cross over to nilotinib. Two hundred and forty-eight patients enrolled. Median PFS was similar between arms (nilotinib 109 days, BSC 111 days P=0.56). Local investigator-based intent-to-treat (ITT) analysis showed a significantly longer median PFS with nilotinib (119 versus 70 days P=0.0007). A trend in longer median overall survival (OS) was noted with nilotinib (332 versus 280 days P=0.29). Post hoc subset analyses in patients with progression and only one prior regimen each of imatinib and sunitinib revealed a significant difference in median OS of >4 months in favor of nilotinib (405 versus 280 days P=0.02). Nilotinib was well tolerated. In the ITT analysis, no significant difference in PFS was observed between treatment arms based on CRR. In the post hoc subset analyses, nilotinib provided significantly longer median OS.
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486664.V1
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Control of NF ‐kB activity in human melanoma by bromodomain and extra‐terminal protein inhibitor I ‐BET 151
Publisher: Wiley
Date: 03-07-2014
DOI: 10.1111/PCMR.12282
Abstract: The transcription factor NF-kappaB (NF-kB) is a key regulator of cytokine and chemokine production in melanoma and is responsible for symptoms such as anorexia, fatigue, and weight loss. In addition, NF-kB is believed to contribute to progression of the disease by upregulation of cell cycle and anti-apoptotic genes and to contribute to resistance against targeted therapies and immunotherapy. In this study, we have examined the ability of the bromodomain and extra-terminal (BET) protein inhibitor I-BET151 to inhibit NF-kB in melanoma cells. We show that I-BET151 is a potent, selective inhibitor of a number of NF-kB target genes involved in induction of inflammation and cell cycle regulation and downregulates production of cytokines such as IL-6 and IL-8. SiRNA studies indicate that BRD2 is the main BET protein involved in regulation of NF-kB and that I-BET151 caused transcriptional downregulation of the NF-kB subunit p105 50. These results suggest that BET inhibitors may have an important role in treatment of melanoma where activation of NF-kB may have a key pathogenic role.
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486670.V1
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
The genomic landscape of phaeochromocytoma
Publisher: Wiley
Date: 02-02-2015
DOI: 10.1002/PATH.4503
Correlation of Subjective Self-reported Melanoma Growth Rate With Objective Tumor Proliferation Markers
Publisher: American Medical Association (AMA)
Date: 04-2008
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486664
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Supplementary Data from γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543542.V1
Abstract: RNA-seq and scRNA-seq count data and TCR contigs
The Epigenetic Regulator I-BET151 Induces BIM-Dependent Apoptosis and Cell Cycle Arrest of Human Melanoma Cells
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1038/JID.2014.243
Abstract: Epigenetic changes are widespread in melanoma and contribute to the pathogenic biology of this disease. In the present study, we show that I-BET151, which belongs to a new class of drugs that target the BET family of epigenetic "reader" proteins, inhibits melanoma growth in vivo and induced variable degrees of apoptosis in a panel of melanoma cells. Apoptosis was caspase dependent and associated with G1 cell cycle arrest. All melanoma cells tested had increased levels of the BH3 proapoptotic protein BIM, which appeared to be regulated by the BRD2 BET protein and to some extent by BRD3. In contrast, knockdown experiments indicated that inhibition of BRD4 was associated with decreased levels of BIM. Apoptosis was dependent on BIM in some but not all cell lines, indicating that other factors were determinants of apoptosis, such as downregulation of antiapoptotic proteins revealed in gene expression arrays. G1 cell cycle arrest appeared to be mediated by p21 and resulted from inhibition of the BRD4 protein. The activity of BET protein inhibitors appears independent of the BRAF and NRAS mutational status of melanoma, and further studies to assess their therapeutic role in melanoma are warranted.
Ipilimumab in pretreated patients with unresectable or metastatic cutaneous, uveal and mucosal melanoma
Publisher: AMPCo
Date: 07-2014
DOI: 10.5694/MJA13.10448
Abstract: To evaluate the efficacy and tolerability of ipilimumab in an Australian clinical setting, and to assess the association of response with melanoma subtype, BRAF mutation status, absolute lymphocyte count and incidence of serious immune-related adverse events (AEs). Retrospective review of patients with unresectable or metastatic melanoma treated with ipilimumab at an Australian oncology centre between July 2010 and April 2012. Overall survival (OS), progression-free survival (PFS), incidence and severity of AEs. 104 patients were retrospectively followed for a median of 7 months (range 0-30 months). Median OS was 9.6 months (95% CI, 6.6-12.4), and median PFS was 3.0 months (95% CI, 2.7-3.4). The 1- and 2-year survival rates were 42% (95% CI, 32%-52%) and 18% (95% CI, 9%-30%), respectively. Median OS for patients with non-cutaneous (mucosal and uveal) melanomas was almost half that of patients with cutaneous melanoma: 5.8 months (95% CI, 2.8-12.4) v 11.7 months (95% CI, 7.1-13.8) P = 0.11. Raised absolute lymphocyte count was associated with increased PFS (P ≤ 0.005 at all measured time points) but not with OS (P > 0.15). Sex, age, brain metastases, BRAF mutation status, incidence of severe immune-related AEs and baseline lactate dehydrogenase levels did not affect OS or PFS (P > 0.05). Eighteen of 104 patients experienced serious AEs (≥ grade 3), including two treatment-related deaths. In an Australian clinical practice setting, ipilimumab achieved efficacy and tolerability measures similar to those reported in clinical trials. The frequency and severity of ipilimumab-related AEs (including death) are notable, and treatment should occur under the supervision of an experienced clinical team.
Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study
Publisher: Elsevier BV
Date: 03-2014
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486661
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?
Publisher: Springer Science and Business Media LLC
Date: 20-04-2022
DOI: 10.1038/S41698-022-00273-9
Abstract: CDK4/6 inhibitors (CDK4/6i) were developed as a cancer therapeutic on the basis of their tumor-intrinsic cytostatic potential, but have since demonstrated profound activity as immunomodulatory agents. While currently approved to treat hormone receptor-positive breast cancer, these inhibitors are under investigation in clinical trials as treatments for a range of cancer types, including melanoma. Melanoma is a highly immunogenic cancer, and has always been situated at the forefront of cancer immunotherapy development. Recent revelations into the immunotherapeutic activity of CDK4/6i, therefore, have significant implications for the utility of these agents as melanoma therapies. In recent studies, we and others have proven the immunomodulatory effects of CDK4/6i to be multifaceted and complex. Among the most notable effects, CDK4/6 inhibition induces transcriptional reprogramming in both tumor cells and immune cells to enhance tumor cell immunogenicity, promote an immune-rich tumor microenvironment, and skew T cell differentiation into a stem-like phenotype that is more amenable to immune checkpoint inhibition. However, in some contexts, the specific immunomodulatory effects of CDK4/6i may impinge on anti-tumor immunity. For ex le, CDK4/6 inhibition restricts optimal T cells expansion, and when used in combination with BRAF/MEK-targeted therapies, depletes immune-potentiating myeloid subsets from the tumor microenvironment. We propose that such effects, both positive and negative, may be mitigated or exacerbated by altering the CDK4/6i dosing regimen. Here, we discuss what the most recent insights mean for clinical trial design, and propose clinical considerations and strategies that may exploit the full immunotherapeutic potential of CDK4/6 inhibitors.
Molecular and Clinical Analysis of Locally Advanced Dermatofibrosarcoma Protuberans Treated With Imatinib: Imatinib Target Exploration Consortium Study B2225
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2005
Abstract: The cutaneous malignant tumor dermatofibrosarcoma protuberans (DFSP) is typically associated with a translocation between chromosomes 17 and 22 that places the platelet-derived growth factor–B (PDGFB) under the control of the collagen 1A1 promoter. The purpose of this study was to evaluate molecular, cytogenetic, and kinase activation profiles in a series of DFSPs and to determine whether these biologic parameters are correlated with the clinical responses of DFSP to imatinib. We analyzed the objective radiologic and clinical response to imatinib at 400 mg twice daily in eight patients with locally advanced DFSP and two patients with metastatic disease. Each of eight patients with locally advanced DFSP had evidence of t(17 ) and showed a clinical response to imatinib. Four of these patients had complete clinical responses. The two patients with metastatic disease had fibrosarcomatous histology and karyotypes that were substantially more complex than those typically associated with localized DFSP. One patient with metastatic DFSP and an associated t(17 ) had a partial response to imatinib but experienced disease progression after 7 months of therapy. In contrast, the other patient with metastatic disease had a tumor lacking t(17 ), and there was no clinical response to imatinib. Unexpectedly, there was minimal platelet-derived growth factor receptor–beta phosphorylation in the untreated DFSP, despite the documented presence of a PDGFB autocrine mechanism. Imatinib has clinical activity against both localized and metastatic DFSP with t(17 ). However, fibrosarcomatous variants of DFSP lacking t(17 ) may not respond to imatinib.
Integration of Immuno-Oncology and Palliative Care
Publisher: American Society of Clinical Oncology (ASCO)
Date: 05-2016
Response of BRAF-Mutant Melanoma to BRAF Inhibition Is Mediated by a Network of Transcriptional Regulators of Glycolysis
Publisher: American Association for Cancer Research (AACR)
Date: 04-2014
DOI: 10.1158/2159-8290.CD-13-0440
Abstract: Deregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF-mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF-mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including hypoxia-inducible factor-1α, MYC, and MONDOA (MLXIP), drives glycolysis downstream of BRAFV600, is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)–resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors. Significance: BRAFis suppress glycolysis and provide strong clinical benefit in BRAFV600 melanoma. We show that BRAF inhibition suppresses glycolysis via a network of transcription factors that are critical for complete BRAFi responses. Furthermore, we provide evidence for the clinical potential of therapies that combine BRAFis with glycolysis inhibitors. Cancer Discov 4(4) 423–33. ©2014 AACR. See related commentary by Haq, p. 390 This article is highlighted in the In This Issue feature, p. 377
Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial
Publisher: Elsevier BV
Date: 09-2016
coBRIM: a phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAFV600 mutation–positive patients with unresectable locally advanced
Publisher: Springer Science and Business Media LLC
Date: 2015
Supplementary Figures from Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543851
Abstract: Supplementary Figures S1-S5
Clustered somatic mutations are frequent in transcription factor binding sites in melanoma and other cutaneous malignancies.
Publisher: Elsevier BV
Date: 02-2016
Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53
Publisher: Elsevier BV
Date: 07-2012
Clinical and pathological associations of the activating RAC1 P29S mutation in primary cutaneous melanoma.
Publisher: Wiley
Date: 04-08-2014
DOI: 10.1111/PCMR.12295
Abstract: Activating mutations in the GTPase RAC1 are a recurrent event in cutaneous melanoma. We investigated the clinical and pathological associations of RAC1(P29S) in a cohort of 814 primary cutaneous melanomas with known BRAF and NRAS mutation status. The RAC1(P29S) mutation had a prevalence of 3.3% and was associated with increased thickness (OR=1.6 P = 0.001), increased mitotic rate (OR=1.3 P = 0.03), ulceration (OR=2.4 P = 0.04), nodular subtype (OR=3.4 P = 0.004), and nodal disease at diagnosis (OR=3.3 P = 0.006). BRAF mutant tumors were also associated with nodal metastases (OR=1.9 P = 0.004), despite being thinner at diagnosis than BRAF WT (median 1.2 mm versus 1.6 mm, P < 0.001). Immunohistochemical analysis of 51 melanomas revealed that 47% were immunoreactive for RAC1. Melanomas were more likely to show RAC1 immunoreactivity if they were BRAF mutant (OR=5.2 P = 0.01). RAC1 may therefore be important in regulating the early migration of BRAF mutant tumors. RAC1 mutations are infrequent in primary melanomas but may accelerate disease progression.
Health-related quality of life in patients with melanoma brain metastases treated with immunotherapy
Publisher: Future Medicine Ltd
Date: 06-2023
Abstract: Aims: To describe the health-related quality of life (HRQoL) of melanoma brain metastasis (MBM) patients throughout the first 18 weeks of ipilimumab–nivolumab or nivolumab treatment. Materials & methods: HRQoL data (European Organisation for Research and Treatment of Cancer's Core Quality of Life Questionnaire, additional Brain Neoplasm Module, and EuroQol 5-Dimension 5-Level Questionnaire) were collected as a secondary outcome of the Anti-PD1 Brain Collaboration phase II trial. Mixed linear modeling assessed changes over time, whereas the Kaplan–Meier method was used to determine median time to first deterioration. Results: Asymptomatic MBM patients treated with ipilimumab–nivolumab (n = 33) or nivolumab (n = 24) maintained baseline HRQoL. MBM patients with symptoms or leptomeningeal rogressive disease treated with nivolumab (n = 14) reported a statistically significant trend toward improvement. Conclusion: MBM patients treated with either ipilimumab–nivolumab or nivolumab did not report a significant deterioration in HRQoL within 18 weeks of treatment initiation. Clinical trial registration: NCT02374242 ( ClinicalTrials.gov )
Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer
Publisher: Springer Science and Business Media LLC
Date: 24-06-2009
The Drug Vehicle and Solvent N-Methylpyrrolidone Is an Immunomodulator and Antimyeloma Compound
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.CELREP.2014.04.008
Abstract: N-methyl-2-pyrrolidone (NMP) is a common solvent and drug vehicle. We discovered unexpected antineoplastic and immunomodulatory activity of NMP in a cMYC-driven myeloma model. Coincident to this, NMP was identified as an acetyllysine mimetic and candidate bromodomain ligand. Accordingly, NMP-treated cells demonstrated transcriptional overlap with BET-bromodomain inhibition, including downregulation of cMYC and IRF4. NMP's immunomodulatory activity occurred at sub-BET inhibitory concentrations, and, despite phenotypic similarities to lenalidomide, its antimyeloma activity was independent of the IMiD targets cereblon and Ikaros-1/3. Thus, low-affinity yet broad-spectrum bromodomain inhibition by NMP mediates biologically potent, cereblon-independent immunomodulation and at higher doses targets malignant cells directly via BET antagonism. These data reveal that NMP is a functional acetyllysine mimetic with pleotropic antimyeloma and immunomodulatory activities. Our studies highlight the potential therapeutic benefits of NMP, the consequences of current human NMP exposures, and the need for reassessment of scientific literature where NMP was used as an "inert" drug-delivery vehicle.
Crystal Structure and Local Structure of Mg2–xPrxNi4 (x = 0.6 and 1.0) Deuteride Using in Situ Neutron Total Scattering
Publisher: American Chemical Society (ACS)
Date: 31-05-2013
DOI: 10.1021/IC400528U
Abstract: We studied crystal structure and local structure of Mg(2-x)Pr(x)Ni4 (x = 0.6 and 1.0) and their deuterides using in situ neutron total scattering and first-principles calculations. The total scattering data were analyzed using Rietveld refinement and pair distribution function analysis (PDF). The crystal structure of Mg(2-x)Pr(x)Ni4 before deuterium absorption was C15b in space group F43m. No difference between the crystal and local (PDF) structures was observed. The crystal structure of Mg1.0Pr1.0Ni4D(∼4) was found to be orthorhombic in space group Pmn2(1), with three deuterium occupation sites: PrNi3 and two types of bipyramidal Pr2MgNi2 that have a plane of symmetry composed of MgNi2. There is no significant difference between the crystal structure and the local structure of Mg1.0Pr1.0Ni4D(∼4). On the other hand, the average crystal structure of the Mg-rich Mg1.4Pr0.6Ni4D(∼3.6) was C15b with two deuterium occupation sites: PrNi3 and MgPrNi2 suggesting that the deuterium occupation shifts away from the Pr2MgNi2 bipyramid. First-principles relaxed structures also showed the shift of the hydrogen occupation site toward the Pr atom of the bipyramid, when induced by Mg substitution for the opposing Pr, resulting in hydrogen occupation in the MgPrNi2 tetrahedral site. The PDF pattern of Mg1.4Pr0.6Ni4D(∼3.6) cannot be refined below 7.2 Å in atomic distances using the C15b structure which was obtained from Rietveld refinement but can be done using an orthorhombic structure. It suggests that Mg1.4Pr0.6Ni4D(∼3.6) was locally distorted to the orthorhombic.
Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-06-2007
Abstract: To evaluate tumor response, pharmacodynamic effects, and safety of a combination of lomeguatrib (LM), an O 6 -methylguanine DNA-methyltransferase (MGMT) inactivator, and temozolomide (TMZ), TMZ alone, and LM/TMZ after disease progression on TMZ alone in patients with advanced melanoma. Patients with unresectable stage III or IV cutaneous melanoma who had no prior systemic chemotherapy were randomly assigned to receive either 40 to 80 mg LM and 125 mg/m 2 TMZ or 200 mg/m 2 TMZ on days 1 through 5 of each 28-day treatment cycle. Drugs were administered orally for up to six cycles of treatment. Patients on TMZ alone were offered LM/TMZ at progression, if fit enough to receive treatment. One hundred four patients were enrolled, with 52 in each trial arm. Twenty-seven TMZ-treated patients received LM/TMZ after progression on TMZ. Unexpectedly, analysis of tumor biopsies showed rapid recovery of MGMT after LM/TMZ with 40 mg/d LM. Therefore, doses of LM were escalated to 60 then 80 mg/d. Tumor response rates were 13.5% with LM/TMZ and 17.3% with TMZ alone. No patient responded to LM/TMZ having progressed through TMZ. Median time to disease progression was 65.5 days for LM/TMZ and 68 days for TMZ. All treatments were well tolerated, although hematologic and gastrointestinal adverse events were common. A higher incidence of hematological adverse events was observed in the LM/TMZ combination arm. The efficacy of LM and TMZ in the current dosing schedule is similar to that of TMZ alone. To maintain MGMT depletion in tumor dosing of LM needs to be continued beyond that of TMZ.
Supplementary Data from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486697
Abstract: Supplementary Data from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Differential 18F-FDG and 3′-Deoxy-3′-18F-Fluorothymidine PET Responses to Pharmacologic Inhibition of the c-MET Receptor in Preclinical Tumor Models
Publisher: Society of Nuclear Medicine
Date: 15-07-2011
DOI: 10.2967/JNUMED.110.086967
Abstract: The ability of PET to image functional changes in tumors is increasingly being used to evaluate response and predict clinical benefit to conventional and novel cancer therapies. Although the use of (18)F-FDG PET is well established, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET has potential advantages as a more specific marker of cellular proliferation. c-MET signaling is frequently dysregulated in cancer and is therefore an attractive therapeutic target. Crizotinib (PF-2341066) is a novel adenosine triphosphate-competitive c-MET kinase inhibitor with antitumor activity in a range of tumor models. The aim of this study was to investigate the utility of PET of glucose metabolism and cell proliferation to monitor tumor response to crizotinib in 2 cell lines with aberrant c-MET signaling. Mice bearing GTL-16 or U87MG xenografts were evaluated for changes in tumor volume and (18)F-FDG and (18)F-FLT uptake after daily oral treatment with up to 50 mg/kg crizotinib. GTL-16 and U87MG cells were treated with crizotinib in vitro and analyzed for (3)H-2-deoxyglucose uptake and expression of activated MET, AKT, and ERK by immunoblotting. Treatment of c-MET- lified GTL-16 xenografts with 50 mg/kg crizotinib caused tumor regression that was associated with a slow reduction in (18)F-FDG uptake (P < 0.05, day 13) and reduced expression of the glucose transporter 1, GLUT-1. Although baseline (18)F-FDG uptake into U87MG tumors was substantially higher than in GTL-16 tumors, (18)F-FDG uptake into U87MG tumors remained unchanged on treatment at 50 mg/kg crizotinib, despite tumor growth inhibition of 93% on day 8 of treatment. These findings were confirmed in vitro, where treatment of U87MG cells with 1 μM crizotinib had no demonstrable effect on glucose uptake. Furthermore, these cells demonstrated constitutive, crizotinib-independent phosphoinositide 3-kinase pathway signaling as demonstrated by phosphorylated AKT and ribosomal protein S6. Both U87MG and GTL-16 tumors showed high baseline uptake of (18)F-FLT, which was reduced by 50% and 53% on days 4 and 8 of treatment, respectively. While the results provide a strong rationale to investigate the use of (18)F-FLT PET as a clinical biomarker for monitoring tumor response to c-MET inhibition, (18)F-FDG PET may be a less robust marker.
Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486694
Abstract: Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
AKT signalling is required for ribosomal RNA synthesis and progression of E μ‐Myc B ‐cell lymphoma in vivo
Publisher: Wiley
Date: 13-02-2013
DOI: 10.1111/FEBS.12135
Abstract: The dysregulation of PI3K/AKT/mTORC1 signalling and/or hyperactivation of MYC are observed in a high proportion of human cancers, and together they form a 'super signalling' network mediating malignancy. A fundamental downstream action of this signalling network is up-regulation of ribosome biogenesis and subsequent alterations in the patterns of translation and increased protein synthesis, which are thought to be critical for AKT/MYC-driven oncogenesis. We have demonstrated that AKT and MYC cooperate to drive ribosomal DNA (rDNA) transcription and ribosome biogenesis, with AKT being essential for rDNA transcription and in vitro survival of lymphoma cells isolated from a MYC-driven model of B-cell lymphoma (Eμ-Myc) [Chan JC et al., (2011) Science Signalling 4, ra56]. Here we show that the allosteric AKT inhibitor MK-2206 rapidly and potently antagonizes rDNA transcription in Eμ-Myc B-cell lymphomas in vivo, and this is associated with a rapid reduction in indicators of disease burden, including spleen weight and the abundance of tumour cells in both the circulation and lymph nodes. Extended treatment of tumour-bearing mice with MK-2206 resulted in a significant delay in disease progression, associated with increased B-cell lymphoma apoptosis. Our findings suggest that malignant diseases characterized by unrestrained ribosome biogenesis may be vulnerable to therapeutic strategies that target the PI3K/AKT/mTORC1/MYC growth control network.
Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials
Publisher: Elsevier BV
Date: 03-2014
A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells.
Publisher: Public Library of Science (PLoS)
Date: 11-12-2015
Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486691
Abstract: Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4+ and CD8+ T cell responses in humans
Publisher: Proceedings of the National Academy of Sciences
Date: 13-07-2004
Abstract: NY-ESO-1 is a “cancer-testis” antigen expressed in many cancers. ISCOMATRIX is a saponin-based adjuvant that induces antibody and T cell responses. We performed a placebo-controlled clinical trial evaluating the safety and immunogenicity of recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant. Forty-six evaluable patients with resected NY-ESO-1-positive tumors received three doses of vaccine intramuscularly at monthly intervals. The vaccine was well tolerated. We observed high-titer antibody responses, strong delayed-type hypersensitivity reactions, and circulating CD8+ and CD4+ T cells specific for a broad range of NY-ESO-1 epitopes, including known and previously unknown epitopes. In an unplanned analysis, vaccinated patients appeared to have superior clinical outcomes to those treated with placebo or protein alone. The vaccine is safe and highly potent immunologically.
An In vivo Tumor Model Exploiting Metabolic Response as a Biomarker for Targeted Drug Development
Publisher: American Association for Cancer Research (AACR)
Date: 11-2005
DOI: 10.1158/0008-5472.CAN-05-2285
Abstract: In vivo models that recapitulate oncogene-dependent tumorigenesis will greatly facilitate development of molecularly targeted anticancer therapies. We have developed a model based on activating mutations in c-KIT in gastrointestinal stromal tumors (GISTs). This model comprises murine tumors of FDC-P1 cell lines expressing c-KIT mutations that render the tumors either responsive (V560G) or resistant (D816V) to the small-molecule c-KIT inhibitor, imatinib. Clinically, GIST response to imatinib is associated with rapid reduction in fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), preceding changes in conventional response criteria by several weeks. Using the FDC-P1 model in small animal PET, FDG uptake into tumors expressing the c-KIT V560G mutation was significantly reduced as early as 4 hours after imatinib treatment. In contrast, no change in FDG uptake was observed in resistant c-KIT D816V-expressing tumors after 48 hours of imatinib treatment. Consistent with the PET results, expression of the glucose transporter, GLUT1, was significantly reduced in V560G tumors at 4 hours, preceding changes in markers of proliferation by several hours. In vitro, imatinib treatment of V560G cells resulted in a reduction of glucose transporter numbers at the cell surface and decreased glucose uptake well before changes in cell viability. Notably, decreased ambient glucose concentrations enhanced the cytotoxic effect of imatinib. Taken together, these data account for the rapidity and significance of the PET response to imatinib and suggest that metabolic effects may contribute to imatinib cytotoxicity. Further, the FDC-P1 model represents a very useful paradigm for molecularly targeted drug development.
Prognostic significance of plasma osteopontin in patients with locoregionally advanced head and neck squamous cell carcinoma treated on TROG 02.02 phase III trial.
Publisher: American Association for Cancer Research (AACR)
Date: 2012
DOI: 10.1158/1078-0432.CCR-11-2295
Abstract: Purpose: High plasma osteopontin (OPN) levels have been reported to be an adverse prognostic factor in head and neck squamous cell carcinomas (HNSCC), correlate with tumor hypoxia, and be predictive of benefit from hypoxia-targeted therapy. We sought to confirm the prognostic and predictive significance of OPN in patients treated on a large international trial. Experimental Design: Patients with stage III/IV HNSCC were randomized to receive definitive radiotherapy concurrently with cisplatin or cisplatin plus the hypoxic cell cytotoxin, tirapazamine (TPZ). Eligibility criteria for this prospective substudy included plasma s le availability for OPN assay by ELISA and absence of major radiation therapy deviations (N = 578). OPN concentrations were analyzed for overall survival (OS) and time to locoregional failure (TTLRF), adjusting for known prognostic factors. Additional analysis was carried out in patients with available tumor p16INK4A staining status. Results: The median OPN level was 544 ng/mL (range: 7–2,640). High OPN levels were not associated with worse OS (relative HR, 1.03 for highest tertile) or TTLRF (relative HR 0.91 for highest tertile). There was no interaction between OPN and treatment arm for OS or TTLRF (P = 0.93 for OS P = 0.87 for TTLRF). For the highest tertile the 2-year OS was 66% on control arm and 67% on TPZ arm (HR = 1.11, P = 0.67). Similarly for p16INK4A negative patients in the highest tertile, the 2-year OS was 61% on control arm and 63% on TPZ arm (HR = 1.05, P = 0.86). Conclusions: We found no evidence that high plasma OPN levels were associated with an adverse prognosis in HNSCC, or were predictive of benefit with hypoxia targeting therapy. Clin Cancer Res 18(1) 301–7. ©2011 AACR.
Mutations in KIT occur at low frequency in melanomas arising from anatomical sites associated with chronic and intermittent sun exposure
Publisher: Wiley
Date: 20-01-2010
TableS1.xlsx from CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540160.V1
Abstract: Supplementary Table S1
Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma.
Publisher: Wiley
Date: 22-06-2011
Targeting Oncogenic Drivers and the Immune System in Melanoma
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2013
Abstract: Melanoma is one of the most common cancers in Western countries but has defied the trend of reductions in age-adjusted mortality observed in most other cancers in recent years. Biologically, melanoma is characterized by a high propensity to metastasize at low tumor volumes necessitating the need for effective drug therapies to support efforts in prevention and early detection for reducing mortality. Efforts to study the clinical biology of melanoma have led to a new understanding of the disease, with genomic studies identifying several targetable oncogenes, in particular the protein kinases BRAF and KIT. Biologic studies have also identified a variety of immunologic targets, including the programmed death 1 (PD-1) and cytotoxic T-cell lymphocyte–associated antigen 4 (CTLA-4) inhibitory molecules expressed on T lymphocytes. After several decades of clinical trials that failed to demonstrate improvement in overall survival in patients with advanced melanoma, small molecule inhibitors of BRAF or MEK and inhibition of CTLA-4 can improve survival in patients with advanced disease. These early clinical studies have provided a great opportunity to improve mortality in melanoma with the significant potential of combinations of signaling inhibitors or signaling inhibitors combined with immunologic agents, particularly when used in the adjuvant setting, and to transform the care of patients with this most challenging of cancers.
Molecularly targeted treatment for dermatofibrosarcoma protuberans
Publisher: Elsevier BV
Date: 04-2004
DOI: 10.1053/J.SEMINONCOL.2004.03.038
Abstract: Traditionally, treatment for dermatofibrosarcoma protuberans (DFSP), a rare cutaneous tumor that is locally aggressive, has been limited to wide surgical excision with negative margins. Although not usually metastatic, DFSP has significant potential for recurrence and interference in local structures. The pathogenesis of DFSP stems from a chromosomal rearrangement involving chromosomes 17 and 22, in which the collagen 1alpha1 gene is fused to the gene for platelet-derived growth factor (PDGF) B-chain. The resultant deregulated expression of PDGFB leads to continuous activation of the PDGF receptor beta (PDGFRbeta) protein-tyrosine kinase that promotes DFSP tumor cell growth. Imatinib is a potent and specific inhibitor of several protein-tyrosine kinases, including the PDGFRs. Preclinical investigations and clinical reports have shown the efficacy of imatinib in DFSP. Imatinib may provide an alternative for the treatment of unresectable or partially resectable tumors, thereby possibly improving the effectiveness of surgery.
Combined CDK4/6 and PI3Kα inhibition is synergistic and immunogenic in triple negative breast cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 14-11-2017
DOI: 10.1158/0008-5472.CAN-17-2210
Abstract: New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wild-type TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell-cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy. Combined PI3Kα and CDK4/6 inhibition significantly increased tumor-infiltrating T-cell activation and cytotoxicity and decreased the frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined PI3Kα and CDK4/6 inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (& year) of established TNBC tumors in vivo. Overall, our results illustrate convergent mechanisms of PI3Kα and CDK4/6 blockade on cell-cycle progression, DNA damage response, and immune-modulation and may provide a novel therapeutic approach for TNBC. Cancer Res 77(22) 6340–52. ©2017 AACR.
Melanoma and immunotherapy bridge 2015
Publisher: Springer Science and Business Media LLC
Date: 07-2016
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486679
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Real‐world treatment patterns and outcomes among metastatic cutaneous melanoma patients treated with ipilimumab
Publisher: Wiley
Date: 08-11-2017
DOI: 10.1111/JDV.14633
Abstract: There is a scarcity of real-world data on treatment patterns and outcomes among advanced melanoma patients treated with immunotherapies including ipilimumab, an anti-CTLA-4 antibody approved since 2011. To evaluate ipilimumab and postipilimumab treatment patterns and outcomes among patients with advanced melanoma in Australia, Germany, Italy and Spain, following regulatory approval. Retrospective multicentre, multinational, observational chart review study. Data were extracted from the start of ipilimumab therapy until the end of at least 40 weeks of follow-up, or death. Data from 371 patients (Australia, 103 Germany, 152 Italy, 76 Spain, 40) were analysed. Mean age was 65 years 62% were male. Eastern Cooperative Oncology Group performance status (ECOG PS) was 0 or 1 for 94%. In 67%, ipilimumab was initially received as second-line or later therapy. Patients received on average 3.4 ipilimumab doses. The ipilimumab-refractory cohort comprised of 226 patients. Of these, 17% in Australia, 47% in Germany, 29% in Italy and 14% in Spain received another antimelanoma treatment after ipilimumab including chemotherapy in 26% and BRAF/other kinase inhibitors in 11%. Ipilimumab-refractory patients who received postipilimumab treatment showed a 40% reduced hazard of dying than those not receiving treatment after ipilimumab (HR 0.60 95% CI 0.43-0.83), after adjustment for potential confounders. During the time observed, ipilimumab was mainly used as second-line or later therapy. A significant proportion of patients received postipilimumab therapy, most of which was chemotherapy. Nevertheless, overall survival following progression on ipilimumab treatment remained poor, highlighting the need for research to develop more effective end-of-life treatment options.
Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes
Publisher: Impact Journals, LLC
Date: 12-08-2015
Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486688
Abstract: Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486685
Abstract: Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
KIT immunohistochemistry and mutation status in gastrointestinal stromal tumours (GISTs) evaluated for treatment with imatinib.
Publisher: Wiley
Date: 27-06-2006
DOI: 10.1111/J.1365-2559.2006.02464.X
Abstract: With the availability of effective but expensive treatment in the form of imatinib, accurate diagnosis of gastrointestinal stromal tumour (GIST) is extremely important. The aims of this study were: to describe the clinicopathological, immunohistochemical and molecular features of cases referred to a cancer centre with a possible diagnosis of GIST to identify pitfalls in the performance and interpretation of KIT immunohistochemistry to define the role of KIT mutation testing in making a diagnosis of GIST. Morphological review, KIT immunohistochemistry and mutation testing were performed on all cases referred with a diagnosis of GIST or where the diagnosis was under serious consideration on the basis of KIT immunopositivity with a view to treating with imatinib. Thirty-seven cases met the inclusion criteria. Of these, 26 were classified as GIST and 11 as non-GIST. Most GISTs showed strong diffuse membranous, cytoplasmic or paranuclear KIT immunopositivity. Some non-GISTs demonstrated patchy cytoplasmic KIT immunopositivity related to the immunohistochemical protocol used in the external laboratory, which led to erroneous diagnoses of GIST in nine (24%) cases. KIT mutations involving exons 11 or 9 were identified in 22 (88%) GISTs tested and none of the non-GISTs. An accurate diagnosis of GIST can be made on clinicopathological and immunohistochemical criteria without the need for mutational analysis in most cases, provided proper attention is paid to the immunohistochemical protocol used and, most importantly, control material. False-positive diagnoses of GIST potentially leading to inappropriate treatment with imatinib are more common than missed diagnoses.
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486676.V1
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486682
Abstract: Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Adjuvant Interferon in Melanoma: Is Duration of Therapy Important?
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-01-2014
Fulminant response to combined checkpoint inhibition with ipilimumab plus nivolumab after failure of nivolumab monotherapy in metastatic melanoma
Publisher: Elsevier BV
Date: 09-2017
Frequency of fibroblast growth factor receptor 1 gene amplification in oral tongue squamous cell carcinomas and associations with clinical features and patient outcome.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.ORALONCOLOGY.2013.01.006
Abstract: Novel therapies are required for patients with recurrent or metastatic oral tongue squamous cell carcinoma (OTSCC). Fibroblast Growth Factor Receptor 1 (FGFR1) lification frequently occurs in squamous cell carcinoma of the lung and represents a novel druggable therapeutic target in this and other malignancies. This study examined the frequency and clinical associations of FGFR1 lification in OTSCC. The frequency of FGFR1 lification determined by fluorescence in situ hybridization was evaluated in a cohort of 123 OTSCC patients. Associations of FGFR1 lification with clinical characteristics and outcome were determined. FGFR1 gene lification was present in 9.3% (10/107) of cases and was significantly associated with smoking status (P = 0.03). FGFR1 lification was seen more commonly in males (9/10 lified cases male, P = 0.16) and there were no associations with age, stage, T stage, nodal status, alcohol history or performance status (all P>0.05). Outcome was not significantly different between FGFR1 lified and non- lified patients. Copy number variations of the FGFR1 gene occur in a subset of OTSCC with approximately 10% of cases showing lification of the gene. FGFR1 lification may represent a therapeutic target in OTSCC.
Mutation analysis for systemic mastocytosis
Publisher: Elsevier BV
Date: 2011
A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors
Publisher: Elsevier BV
Date: 06-2011
Splicing the way to leukemia with KIT
Publisher: Informa UK Limited
Date: 2008
Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-01-2022
DOI: 10.1200/JCO.21.02229
Abstract: In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes. Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated. Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF-mutant tumors and 46%, 42%, and 22% in those with BRAF–wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed. These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Publisher: Massachusetts Medical Society
Date: 02-07-2015
Supplementary Data DS1 from A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in <i>BRAF</i> V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490194.V1
Abstract: Supplementary material
Survival of patients with advanced metastatic melanoma: The impact of novel therapies
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.EJCA.2015.09.013
Abstract: The survival of advanced metastatic melanoma has been greatly improved within the past few years. New therapeutic strategies like kinase inhibitors for BRAF-mutant melanoma and immune checkpoint blockers proved to prolong survival times within clinical trials, and many of them have already entered routine clinical use. However, these different treatment modalities have not yet been tested against each other, which complicate therapy decisions. We performed an explorative analysis of survival data from recent clinical trials. Thirty-five Kaplan-Meier survival curves from 17 trials were digitised, re-grouped by matching inclusion criteria and treatment line, and averaged by therapy strategy. Notably, the survival curves grouped by therapy strategy revealed a very high concordance, even if different agents were used. The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes. For first-line therapy, averaged survival proportions of patients alive at 12 months were 74.5% with BRAF plus MEK inhibitor treatment versus 71.9% with PD-1 blockade. This explorative comparison shows the kinase inhibitors as similarly effective as immune checkpoint blockers with regard to survival. However, to confirm these first trends for implementation into an in idualised treatment of melanoma patients, data from prospective clinical trials comparing the different treatment strategies head-to-head have to be awaited.
UBF levels determine the number of active ribosomal RNA genes in mammals
Publisher: Rockefeller University Press
Date: 22-12-2008
Abstract: In mammals, the mechanisms regulating the number of active copies of the ∼200 ribosomal RNA (rRNA) genes transcribed by RNA polymerase I are unclear. We demonstrate that depletion of the transcription factor upstream binding factor (UBF) leads to the stable and reversible methylation-independent silencing of rRNA genes by promoting histone H1–induced assembly of transcriptionally inactive chromatin. Chromatin remodeling is abrogated by the mutation of an extracellular signal-regulated kinase site within the high mobility group box 1 domain of UBF1, which is required for its ability to bend and loop DNA in vitro. Surprisingly, rRNA gene silencing does not reduce net rRNA synthesis as transcription from remaining active genes is increased. We also show that the active rRNA gene pool is not static but decreases during differentiation, correlating with diminished UBF expression. Thus, UBF1 levels regulate active rRNA gene chromatin during growth and differentiation.
Distinct clinical and pathological features are associated with the BRAF(T1799A(V600E)) mutation in primary melanoma.
Publisher: Elsevier BV
Date: 04-2007
Abstract: The BRAF(T1799A) mutation encodes BRAF(V600E) that leads to activation of the mitogen-activated protein kinase pathway. This study aimed to assess the clinico-pathological features of primary invasive melanomas containing the BRAF(T1799A) mutation. Patients (n=251) with invasive primary melanomas from Australia were interviewed and examined with respect to their melanoma characteristics and risk factors. Independent review of pathology, allele-specific PCR for the BRAF(T1799A) mutation, immunohistochemical staining with Ki67, and phospho-histone-H3 (PH3) were performed. The BRAF(T1799A) mutation was found in 112 (45%) of the primary melanomas. Associations with the BRAF(T1799A) mutation (P<0.05) were as follows: low tumor thickness (odds ratio (OR)=3.3) low mitotic rate (OR=2.0) low Ki67 score (OR=5.0) low PH3 score (OR=3.3) superficial spreading melanoma (OR=10.0) pigmented melanoma (OR=3.7) a lack of history of solar keratoses (OR=2.7) a location on the trunk (OR=3.4) or extremity (OR=2.0) a high level of self-reported childhood sun exposure (OR=2.0) < or =50 years of age (OR=2.5) and fewer freckles (OR=2.5). We conclude that the BRAF(T1799A) mutation has associations with host phenotype, tumor location, and pigmentation. Although implicated in the control of the cell cycle, the BRAF(T1799A) mutation is associated with a lower rate of tumor proliferation.
γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival
Publisher: American Association for Cancer Research (AACR)
Date: 05-03-2021
DOI: 10.1158/2326-6066.CIR-20-0817
Abstract: Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4+ or CD8+ T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates (& % DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2− γδ T cells. In the context of γδ T–cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T–cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti–PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T–cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions. See related Spotlight on p. 600
The coming of age of MEK
Publisher: Elsevier BV
Date: 08-2012
Biomarker analysis of on-treatment and at progression biopsies from BRIM7 - a phase 1B trial of combined vemurafenib and cobimetinib treatment in BRAF V600 mutated melanoma.
Publisher: Springer Science and Business Media LLC
Date: 05-2014
Efficacy of CHK inhibitors as single agents in MYC-driven lymphoma cells
Publisher: Springer Science and Business Media LLC
Date: 15-08-2011
DOI: 10.1038/ONC.2011.358
Abstract: CHK1 and CHK2 function as effectors of cell cycle checkpoint arrest following DNA damage. Small molecule inhibitors of CHK proteins are under clinical evaluation in combination with chemotherapeutic agents known to induce DNA damage. We examined whether CHK inhibitors could be effective as single agents in malignant cells with inherent DNA damage because of deregulated expression of the oncogene c-Myc. Eμ-myc lymphoma cells showed a dramatic increase in the extent of DNA damage and DNA damage response (DDR) signalling within 1 h of treatment with CHK1 inhibitors followed by caspase-dependent apoptosis and cell death. In p53 wild-type/ARF null Eμ-myc lymphoma cells, apoptotic cell death was preceded by accumulation of DNA damage and the amount of DNA damage correlated with the extent of cell death. This effect was not observed in normal B cells indicating that DNA damage accumulation following CHK inhibition was specific to Eμ-myc lymphoma cells that exhibit inherent DNA damage because of MYC-induced replication stress. Similar results were obtained with another structurally distinct CHK-inhibitor. Eμ-myc p53 null lymphoma cells were more sensitive to a dual CHK1/CHK2 inhibitor than to a CHK1-specific inhibitor. In all cases, the level of DNA damage following treatment was the most consistent indicator of drug sensitivity. Our results suggest that CHK inhibitors would be beneficial therapeutic agents in MYC-driven cancers. We propose that inhibitors of CHK can act in a synthetically lethal manner in cancers with replication stress as a result of these cancers being reliant on CHK proteins for an effective DDR and cell survival.
Multi-tracer small animal PET imaging of the tumour response to the novel pan-Erb-B inhibitor CI-1033
Publisher: Springer Science and Business Media LLC
Date: 02-2006
DOI: 10.1007/S00259-005-0039-5
Abstract: This study was designed as "proof of concept" for a drug development model utilising multi-tracer serial small animal PET imaging to characterise tumour responses to molecularly targeted therapy. Mice bearing subcutaneous A431 human squamous carcinoma xenografts (n=6-8) were treated with the pan-Erb-B inhibitor CI-1033 or vehicle and imaged serially (days 0, 3 and 6 or 7) with [(18)F]fluorodeoxyglucose, [(18)F]fluoro-L: -thymidine, [(18)F]fluoro-azoazomycinarabinoside or [(18)F]fluoromisonidazole. Separate cohorts (n=3) were treated identically and tumours were assessed ex vivo for markers of glucose metabolism, proliferation and hypoxia. During the study period, mean uptake of all PET tracers generally increased for control tumours compared to baseline. In contrast, tracer uptake into CI-1033-treated tumours decreased by 20-60% during treatment. Expression of the glucose transporter Glut-1 and cell cycle markers was unchanged or increased in control tumours and generally decreased with CI-1033 treatment, compared to baseline. Thymidine kinase activity was reduced in all tumours compared to baseline at day 3 but was sevenfold higher in control versus CI-1033-treated tumours by day 6 of treatment. Uptake of the hypoxia marker pimonidazole was stable in control tumours but was severely reduced following 7 days of CI-1033 treatment. CI-1033 treatment significantly affects tumour metabolism, proliferation and hypoxia as determined by PET. The PET findings correlated well with ex vivo biomarkers for each of the cellular processes studied. These results confirm the utility of small animal PET for evaluation of the effectiveness of molecularly targeted therapies and simultaneously definition of specific cellular processes involved in the therapeutic response.
Marked, homogeneous, and early [18F]fluorodeoxyglucose-positron emission tomography responses to vemurafenib in BRAF-mutant advanced melanoma.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-05-2012
Abstract: Imaging with [ 18 F]fluorodeoxyglucose (FDG) –positron emission tomography (PET) allows early recognition of a response to agents that target key driver mutations in human cancer. We aimed to determine the metabolic response rate to vemurafenib in patients with advanced BRAF-mutant melanoma. Baseline and day 15 FDG-PET was evaluated in 31 patients with advanced melanoma treated in a phase I study of dose escalation of vemurafenib (PLX06-02), which included four patients treated at subtherapeutic doses and 24 patients treated at 960 mg twice a day, which is the maximum-tolerated dose of vemurafenib. All 27 patients treated at potentially therapeutic levels had at least a partial metabolic response, and three patients achieved a complete metabolic response. In the 27 patients, there was an 80% ± 3% reduction in the maximum standardized uptake value (SUVmax) of target lesions and an 87% ± 3% decrease in the percentage of injected dose (%ID) in all identified disease sites. There was a positive correlation between %ID in all identified disease and target-lesion SUVmax (r 2 = 0.66 P .001) that indicated a significant homogeneity of the response between lesions in in idual patients. Although no relationship was found between the reduction in target lesion SUVmax and best response according to RECIST (Response Evaluation Criteria in Solid Tumors), there was a trend for patients with greater reductions in uptake of FDG to have longer progression-free survival. FDG-PET is a useful marker of an early biologic response to vemurafenib. Little variability in PET response was found between lesions in in idual patients, which suggested minimal intrapatient molecular heterogeneity. FDG-PET is a useful tool for the evaluation of the biologic impact of inhibiting mutant BRAF and may allow for the more effective development of novel agents.
Navigating the challenge of tumor heterogeneity in cancer therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2014
DOI: 10.1158/2159-8290.CD-13-1042
Abstract: Summary: The future of cancer treatment lies in personalized strategies designed to specifically target tumorigenic cell populations present in an in idual. Although recent advances in directed therapies have greatly improved patient outcomes in some cancers, intuitive drug design is proving more difficult than expected owing largely to the complexity of human cancers. Intratumoral heterogeneity, the presence of multiple genotypically and/or phenotypically distinct cell subpopulations within a single tumor, is a likely cause of drug resistance. Advances in systems biology are helping to unravel the mysteries of cancer progression. In this issue of Cancer Discovery, Zhao and colleagues define a path for functional validation of computational modeling in the context of heterogeneous tumor populations and their potential for drug response and resistance. Cancer Discov 4(2) 146–8. ©2014 AACR. See related article by Zhao et al., p. 166
A Distinct Pretreatment Immune Gene Signature in Lentigo Maligna Is Associated with Imiquimod Response
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.JID.2019.07.725
Abstract: Lentigo maligna (LM) is a common subtype of in situ melanoma on chronically sun-exposed skin, particularly the head and neck of older patients. Although surgery is the standard treatment, there is associated morbidity, and options such as imiquimod cream or radiotherapy may be used if surgery is refused or inappropriate. Complete response rates following imiquimod treatment are variable in the literature. The aim of this study was to evaluate the host immune response both before and following treatment with imiquimod to better identify likely responders. Paired pre- and post-imiquimod treatment specimens were available for 27 patients. Patients were treated with imiquimod 5 days per week for 12 weeks at 16 weeks, lesions were excised for histological assessment. Of the 27 patients, 16 were responders and 11 failed to clear the disease. PDL1 protein expression was increased, accompanied by a unique gene signature in lesions from patients that subsequently histologically cleared LM by 16 weeks. This comprised 57 upregulated immune genes in signaling networks for antigen presentation, type I interferon signaling, and T-cell activation. This may represent an early responder group to imiquimod, and this unique gene signature potentially can be used as a biomarker of LM response to imiquimod.
Novel combination therapies for BRAF-mutant melanoma
Publisher: Springer Science and Business Media LLC
Date: 2015
A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition inBRAFV600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study
Publisher: American Association for Cancer Research (AACR)
Date: 13-01-2023
DOI: 10.1158/1078-0432.CCR-22-3094
Abstract: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET lification. The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.
The Current State of Targeted Therapy in Melanoma: This Time It's Personal
Publisher: Elsevier BV
Date: 04-2012
An inverse stage-shift model to estimate the excess mortality and health economic impact of delayed access to cancer services due to the COVID-19 pandemic
Publisher: Wiley
Date: 10-02-2021
DOI: 10.1111/AJCO.13505
Abstract: Decreased cancer incidence and reported changes to clinical management indicate that the COVID‐19 pandemic has delayed cancer diagnosis and treatment. This study aimed to develop and apply a flexible model to estimate the impact of delayed diagnosis and treatment on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation. A model was developed and made publicly available to estimate population‐level health economic outcomes by extrapolating and weighing stage‐specific outcomes by the distribution of stages at treatment initiation. It was applied to estimate the impact of 3‐ and 6‐month delays based on Australian data for stage I breast cancer, colorectal cancer, and lung cancer patients, and for T1 melanoma. Two approaches were explored to estimate stage shifts following a delay: (a) based on the relation between time to treatment initiation and overall survival (breast, colorectal, and lung cancer), and (b) based on the tumor growth rate (melanoma). Using a conservative once‐off 3‐month delay and considering only shifts from stage I/T1 to stage II/T2, 88 excess deaths and $12 million excess healthcare costs were predicted in Australia over 5 years for all patients diagnosed in 2020. For a 6‐month delay, excess mortality and healthcare costs were 349 deaths and $46 million over 5 years. The health and economic impacts of delays in treatment initiation cause an imminent policy concern. More accurate in idual patient data on shifts in stage of disease during and after the COVID‐19 pandemic are critical for further analyses.
Host immunity contributes to the antimelanoma activity of BRAF inhibitors
Publisher: American Society for Clinical Investigation
Date: 02-2013
DOI: 10.1172/JCI66236
Optimizing combination dabrafenib and trametinib therapy in BRAF mutation-positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists
Publisher: Wiley
Date: 30-11-2016
DOI: 10.1111/AJCO.12656
Abstract: BRAF mutations occur commonly in metastatic melanomas and inhibition of mutant BRAF and the downstream kinase MEK results in rapid tumor regression and prolonged survival in patients. Combined therapy with BRAF and MEK inhibition improves response rate, progression free survival and overall survival compared with single agent BRAF inhibition, and reduces the skin toxicity that is seen with BRAF inhibitor monotherapy. However, this combination is associated with an increase in other toxicities, particularly drug-related pyrexia, which affects approximately 50% of patients treated with dabrafenib and trametinib (CombiDT). We provide guidance on managing adverse events likely to arise during treatment with combination BRAF and MEK inhibition with CombiDT: pyrexia, skin conditions, fatigue and discuss management of CombiDT during surgery and radiotherapy. By improving tolerability and in particular preventing unnecessary treatment cessations or reduction in drug exposure, best outcomes can be achieved for patients undergoing CombiDT therapy.
Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF Inhibition
Publisher: American Society of Clinical Oncology (ASCO)
Date: 07-2012
Abstract: Selective inhibition of mutant BRAF by using class I RAF inhibitors in patients with metastatic melanoma has resulted in impressive clinical activity. However, there is also evidence that RAF inhibitors might induce carcinogenesis or promote tumor progression via stimulation of MAPK signaling in RAF wild-type cells. We analyzed melanocytic lesions arising under class I RAF inhibitor treatment for dignity, specific genetic mutations, or expression of signal transduction molecules. In all, 22 cutaneous melanocytic lesions that had either developed or considerably changed in morphology in 19 patients undergoing treatment with selective BRAF inhibitors for BRAF-mutant metastatic melanoma at seven international melanoma centers within clinical trials in 2010 and 2011 were analyzed for mutations in BRAF and NRAS genes and immunohistologically assessed for expression of various signal transduction molecules in comparison with 22 common nevi of 21 patients with no history of BRAF inhibitor treatment. Twelve newly detected primary melanomas were confirmed in 11 patients within 27 weeks of selective BRAF blockade. In addition, 10 nevi developed of which nine were dysplastic. All melanocytic lesions were BRAF wild type. Explorations revealed that expression of cyclin D1 and pAKT was increased in newly developed primary melanomas compared with nevi (P = .01 and P = .03, respectively). There was no NRAS mutation in common nevi, but BRAF mutations were frequent. Malignant melanocytic tumors might develop with increased frequency in patients treated with selective BRAF inhibitors supporting a mechanism of BRAF therapy–induced growth and tumorigenesis. Careful surveillance of melanocytic lesions in patients receiving class I RAF inhibitors seems warranted.
Supplementary Table S1 from Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543848
Abstract: Supplementary Table S1
Data from γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550308
Abstract: Abstract Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4 sup + /sup or CD8 sup + /sup T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates ( % DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2 sup − /sup γδ T cells. In the context of γδ T–cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T–cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti–PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T–cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions. i See related Spotlight on p. 600 /i /
Radiotherapy complements immune checkpoint blockade
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.CCELL.2015.03.015
Abstract: Adaptive immune resistance ablates effective anti-tumor immune responses. In a recent issue of Nature, Victor and colleagues describe that anti-PD-L1 combats adaptive immune resistance upon localized radiation plus anti-CTLA-4 therapy. The superior activity of radiation and dual immune checkpoint blockade is mediated by non-redundant immune mechanisms in cancer.
Immunotherapy of melanoma
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.EJSO.2016.07.014
Abstract: Immunotherapy for advanced melanoma has progressed dramatically in the last five years with the approval of immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Inhibition of these targets can break cancer-immune tolerance and result in durable objective responses with significantly improved tolerability over cytokine-based immunotherapy. Ipilimumab is an inhibitor of CTLA-4 and the first-in-class immune checkpoint inhibitor to demonstrate an improvement in overall survival in melanoma. Pembrolizumab and nivolumab target PD-1 and have improved single agent activity and tolerability in comparison to ipilimumab. The combination of nivolumab and ipilimumab results in even better response rates, reductions in tumor volume and progression free survival but at the expense of considerable autoimmune effects. Autoimmune side-effects and non-standard response kinetics represent a new challenge associated with cancer therapies that practitioners will have to become more familiar with as checkpoint inhibitors increasingly become part of mainstream oncological practice. Ongoing areas of investigation include drug development against novel immune targets alternative treatment modalities, such as genetically modified oncolytic viruses optimization of immunotherapy combination strategies and the identification of reliable biomarkers to better guide treatment selection.
Updated efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in metastatic melanoma patients previously treated with anti-PD-1 therapy.
Publisher: BMJ
Date: 2015
Rate of Growth in Melanomas
Publisher: American Medical Association (AMA)
Date: 12-2006
DOI: 10.1001/ARCHDERM.142.12.1551
Abstract: To investigate the spectrum of growth rates in melanomas and to identify clinical associations of rapidly growing melanomas. Clinical interview, skin examination, and pathology review. Three tertiary melanoma referral centers and 2 private dermatology practices. A total of 404 consecutive patients with invasive primary cutaneous melanomas. A surrogate for rate of growth in primary invasive melanoma was calculated as the ratio of Breslow thickness to time to melanoma development based on a previously reported assessment tool. One third of the melanomas grew 0.5 mm per month or more. The median monthly growth rate was 0.12 mm for superficial spreading melanomas, 0.13 mm for lentigo maligna melanomas, and 0.49 mm for nodular melanomas. Rapid tumor growth was associated with tumor thickness ( 4 mm, GMR = 12.1) and mitotic rate ( 10/mm(2), GMR = 9.7). Rapid tumor growth occurred more often in males (GMR = 1.7), elderly in iduals (>or=70 years old, GMR = 2.8), and patients with fewer melanocytic nevi (n<50, GMR = 2.0) and fewer freckles (GMR = 2.5). Rapidly growing melanomas were more often symmetrical (GMR = 2.5), elevated (GMR = 1.4), amelanotic (GMR = 1.7), regular in border (GMR = 2.5), and symptomatic (GMR = 1.7). Rapid growth of primary cutaneous melanomas is associated with aggressive histologic features and atypical clinical features. It occurs more frequently in elderly men and in iduals with fewer nevi and fewer freckles.
Molecular targeting of dermatofibrosarcoma protuberans: a new approach to a surgical disease.
Publisher: Harborside Press, LLC
Date: 05-2007
Abstract: Dermatofibrosarcoma protuberans (DFSP) is a low-grade malignancy of the skin and subcutaneous tissues that only rarely forms distant metastases. More than 90% of cases are associated with a chromosomal translocation involving the COL1A1 gene on chromosome 17 and the platelet-derived growth factor B gene on chromosome 22. Management of this disease is primarily surgical with excellent rates of local control obtained using either wide local excision or Mohs micrographic surgery. Data have recently shown that inhibiting platelet-derived growth factor receptors (PDGFR) with imatinib can induce high rates of clinical response in patients with unresectable or metastatic DFSP. These data have led to approval of imatinib by the U.S. Food and Drug Administration for treating uresectable DFSP. Although wide surgical excision remains standard care, patients with locally advanced disease not suitable for surgical excision can be treated with the PDGFR-inhibitor imatinib, which sometimes allows residual DFSP to be surgically excised.
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486661.V1
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Effects of reconstruction of a pre-European vertebrate assemblage on ground-dwelling arachnids in arid Australia
Publisher: Springer Science and Business Media LLC
Date: 21-01-2015
DOI: 10.1007/S00442-014-3189-Y
Abstract: Species loss can result in changes in assemblage structure and ecosystem function through ecological cascades. Australian vertebrate assemblages changed significantly following European colonisation, which resulted in the establishment of invasive vertebrates and the loss of native marsupials, many of which consume invertebrates. Conservation focusses on the removal of invasive carnivores and the reintroduction of regionally extinct species to fenced sites, resulting in what could be considered a reconstruction of pre-European vertebrate assemblages. In semi-arid Australian spinifex mallee ecosystems, we asked: (1) what is the effect of reconstructed pre-European vertebrate assemblages on native arachnid assemblages? and (2) what direct or indirect mechanisms (predation, disturbance and/or competition) could plausibly be responsible for these effects? We compared sites with reconstructed vertebrate assemblages with paired control sites. Arachnids were s led using pitfall trapping and direct searching. Hypotheses regarding mechanisms were tested using scat analysis (predation) and by comparing burrow depth (disturbance) and scorpion mass (competition) between control and reconstructed sites. The dominant dune scorpion, Urodacus yaschenkoi, was less abundant and a wolf spider (Lycosa gibsoni species group) more abundant in reconstructed sites. Differences in spider assemblage composition were marginally non-significant. Scat analysis confirmed native vertebrate predation on scorpions and we found no evidence that competition or disturbance affected scorpions. We, thus, suggest that changes in spider assemblages may have resulted from ecological cascades via decreases in dune scorpions. The loss of omnivorous mammals and other changes associated with the invasion of carnivores may, therefore, have had broad-reaching consequences for native arachnid assemblages in Australian ecosystems.
Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas
Publisher: American Society of Hematology
Date: 11-04-2013
DOI: 10.1182/BLOOD-2012-08-446096
Abstract: MYC-driven lymphomas demonstrate activation of mTORC1 and an endogenous DNA damage response. BEZ235 inhibits PI3K-related DNA damage response kinases and mTORC1, inducing p53-independent upregulation of proapoptotic BMF.
Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma.
Publisher: Springer Science and Business Media LLC
Date: 07-02-2015
DOI: 10.1007/S00262-015-1656-X
Abstract: Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08) however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4(+) T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents.
Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486688.V1
Abstract: Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Supplementary Data DS1 from A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in <i>BRAF</i> V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490194
Abstract: Supplementary material
UV-associated mutations underlie the etiology of MCV-negative Merkel cell carcinomas
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2015
DOI: 10.1158/0008-5472.CAN-15-1877
Abstract: Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or lified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell–infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. Cancer Res 75(24) 5228–34. ©2015 AACR.
Molecular Therapeutic Advances in Personalized Therapy of Melanoma and Non-Small Cell Lung Cancer
Publisher: MDPI AG
Date: 10-04-2012
DOI: 10.3390/JPM2020035
Data from A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in <i>BRAF</i> V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Com
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6533113.V1
Abstract: AbstractPurpose: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. Patients and Methods: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Results: Thirty-two patients with i BRAF /i V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal i KRAS /i , i NRAS /i , and i MAP2K1 /i mutations, and i MET /i lification. Conclusions: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance. /
Data from Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550431
Abstract: Abstract Combined inhibition of BRAF, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a i BRAF sup V600 /sup /i mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic i Braf sup V600E /sup Cdkn2a sup −/− /sup Pten sup −/− /sup /i melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA sequencing analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted proinflammatory macrophages and cross-priming CD103 sup + /sup dendritic cells, the absence of which correlated with poor overall survival and clinical responses to ICB in patients with melanoma. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses i ex vivo /i . While combined BRAF, MEK, and CDK4/6 inhibition demonstrates favorable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact antitumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRAF, MEK, and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma. /
Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486694.V1
Abstract: Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Updated results and correlative FDG-PET analysis of a phase IB study of vemurafenib and cobimetinib (MEK inhibitor [GDC-0973]), in advanced BRAFV600- mutated melanoma (BRIM7).
Publisher: Springer Science and Business Media LLC
Date: 2014
Multiple Gastrointestinal Polyps in Patients Treated with BRAF Inhibitors
Publisher: American Association for Cancer Research (AACR)
Date: 30-11-2015
DOI: 10.1158/1078-0432.CCR-15-0469
Abstract: Purpose: BRAF inhibitors (BRAFi) extend survival in BRAF-mutant melanoma but can promote the growth of Ras-mutant neoplasms. This study determined if gastrointestinal polyps found in BRAFi-treated patients harbored Ras mutations. Experimental Design: Colonic and gastric polyps were identified and resected from BRAFi-treated melanoma patients. Next-generation sequencing (NGS) was performed on polyps. The ability of BRAFi to promote polyp formation was functionally characterized in Apc Min+/− mice. MAPK and β-catenin pathway activity was assessed by immunohistochemistry in mouse and human polyps. Results: Fourteen patients treated with BRAFi underwent endoscopy to assess for polyps. Seven out of 7 patients & years of age and treated for & years were found to have colonic tubular adenomas with 4 out of the 7 patients having 5 or more polyps. One patient presented with bleeding from hyperplastic gastric polyps that recurred 6 months after BRAFi rechallenge. NGS performed on polyps found no mutations in MAPK pathway genes, but found APC mutations in all tubular adenomas. A significant increase in the number of polyps was observed in BRAFi-treated compared with control-treated Apc Min+/− mice (20.8 ± 9.2 vs 12.8 ± 0.1 P = 0.016). No polyps were observed in BRAFi-treated wild-type mice. Conclusions: BRAFi may increase the risk of developing hyperplastic gastric polyps and colonic adenomatous polyps. Due to the risk of gastrointestinal bleeding and the possibility of malignant transformation, further studies are needed to determine whether or not endoscopic surveillance should be recommended for patients treated with BRAFi. Clin Cancer Res 21(23) 5215–21. ©2015 AACR.
Cell cycle control as a promising target in melanoma
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2015
Prognostic and Predictive Significance of Plasma HGF and IL-8 in a Phase III Trial of Chemoradiation with or without Tirapazamine in Locoregionally Advanced Head and Neck Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2012
DOI: 10.1158/1078-0432.CCR-11-2094
Abstract: Purpose: Hepatocyte growth factor (HGF) is a hypoxia-induced secreted protein that binds to cMet and regulates interleukin (IL)-8 expression. We evaluated the role of circulating HGF and IL-8 as prognostic and predictive factors for efficacy of tirapazamine (TPZ), a hypoxic cell cytotoxin. Experimental Design: Patients with stages III to IV head and neck cancer were randomized to receive radiotherapy with cisplatin (CIS) or CIS plus TPZ (TPZ/CIS). Eligibility for the substudy included plasma s le availability for HGF and IL-8 assay by ELISA and no major radiation deviations (N = 498). Analyses included adjustment for major prognostic factors. p16INK4A staining (human papillomavirus surrogate) was carried out on available tumors. Thirty-nine patients had hypoxia imaging with 18F-fluoroazomycin arabinoside (18FAZA)–positron emission tomography. Results: Elevated IL-8 level was associated with worse overall survival (OS) irrespective of treatment. There was an interaction between HGF and treatment arm (P = 0.053) elevated HGF was associated with worse OS in the control but not in the TPZ/CIS arm. Similar trends were observed in analyses restricted to p16INK4A-negative patients. Four subgroups defined by high and low HGF/IL-8 levels were examined for TPZ effect the test for interaction with arm was P = 0.099. TPZ/CIS seemed to be beneficial for patients with high HGF and IL-8 but adverse for low HGF and high IL-8. Only HGF correlated with 18FAZA tumor standard uptake value. Conclusions: IL-8 is an independent prognostic factor irrespective of treatment. There is an interaction between HGF and treatment arm. Certain subgroups based on IL-8/HGF levels seemed to do better with TPZ/CIS while others did worse, highlighting the complexity of hypoxia targeting in unselected patients. Clin Cancer Res 18(6) 1798–807. ©2012 AACR.
Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study
Publisher: Elsevier BV
Date: 10-2017
The Advantages and Challenges of Using FDG PET/CT for Response Assessment in Melanoma in the Era of Targeted Agents and Immunotherapy
Publisher: Springer Science and Business Media LLC
Date: 07-04-2017
DOI: 10.1007/S00259-017-3691-7
Abstract: The treatment of melanoma has been revolutionised in recent years by advances in the understanding of the genomic landscape of this disease, which has led to the development of new targeted therapeutic agents, and the ability to therapeutically manipulate the immune system through inhibition of cancer cell-T-cell interactions that prevent an adaptive immune response. While these therapeutic interventions have dramatically improved the prospects of survival for patients with advanced melanoma, they bring significant complexity to the interpretation of therapeutic response because their mechanisms and temporal profile of response vary considerably. In this review, we discuss the mode of action of these emerging therapies and their toxicities to provide a framework for the use of FDG PET/CT in therapeutic response assessment. We propose that the greatest utility of PET in assessment of response to agents that abrogate signalling related to BRAF mutation is for early assessment of resistance, while in anti-CTLA4 therapy, immunological flare can compromise early assessment of response but can identify potentially life-threatening autoimmune reactions. For anti-PD1/PDL1 therapy, the role of FDG PET/CT is more akin to its use in other solid malignancies undergoing treatment with conventional chemotherapy. However, further research is required to optimise the timing of scans and response criteria in this disease.
Future perspectives in melanoma research. Meeting report from the “Melanoma Bridge. Napoli, December 2nd-4th 2012”
Publisher: Springer Science and Business Media LLC
Date: 03-06-2013
Adjuvant immunotherapy for cancer: the next step
Publisher: Elsevier BV
Date: 05-2015
Incorporation of somatic BRAF mutation testing into an algorithm for the investigation of hereditary non-polyposis colorectal cancer.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2007
DOI: 10.1007/S10689-007-9124-1
Abstract: Patients suspected on clinical grounds to have hereditary non-polyposis colorectal cancer (HNPCC) may be offered laboratory testing in order to confirm the diagnosis and to facilitate screening of pre-symptomatic family members. Tumours from an affected family member are usually pre-screened for microsatellite instability (MSI) and/or loss of immunohistochemical expression of mismatch repair (MMR) genes prior to germline MMR gene mutation testing. The efficiency of this triage process is compromised by the more frequent occurrence of sporadic colorectal cancer (CRC) showing high levels of MSI (MSI-H) due to epigenetic loss of MLH1 expression. Somatic BRAF mutations, most frequently V600E, have been described in a significant proportion of sporadic MSI-H CRC but not in HNPCC-associated cancers. BRAF mutation testing has therefore been proposed as a means to more definitively identify and exclude sporadic MSI-H CRC cases from germline MMR gene testing. However, the clinical validity and utility of this approach have not been previously evaluated in a familial cancer clinic setting. Testing for the V600E mutation was performed on MSI-H CRC s les from 68 in iduals referred for laboratory investigation of suspected HNPCC. The V600E mutation was identified in 17 of 40 (42%) tumours showing loss of MLH1 protein expression by immunohistochemistry but in none of the 28 tumours that exhibited loss of MSH2 expression (P < 0.001). The assay was negative in all patients with an identified germline MMR gene mutation. Although biased by the fact that germline testing was not pursued beyond direct sequencing in many cases lacking a high clinical index of suspicion of HNPCC, BRAF V600E detection was therefore considered to be 100% specific and 48% sensitive in detecting sporadic MSI-H CRC amongst those cases showing loss of MLH1 protein expression, in a population of patients with MSI-H CRC and clinical features suggestive of HNPCC. Accordingly, we recommend the incorporation of BRAF V600E mutation testing into the laboratory algorithm for pre-screening patients with suspected HNPCC, whose CRCs show loss of expression of MLH1. In such tumours, the presence of a BRAF V600E mutation indicates the tumour is not related to HNPCC and that germline testing of MLH1 in that in idual is not warranted. We also recommend that in families where the clinical suspicion of HNPCC is high, germline testing should not be performed on an in idual whose CRC harbours a somatic BRAF mutation, as this may compromise identification of the familial mutation.
TableS1.xlsx from CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540160
Abstract: Supplementary Table S1
Supplementary Figures from CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540163
Abstract: Supplementary Figures 1-12
Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-02-2013
Abstract: In phase I/II trials, the cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy. Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine). In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88 P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor. This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.
Sustained clinical responses to tyrosine kinase inhibitor sunitinib in thyroid carcinoma
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2008
Dermatofibrosarcoma Protuberans: Recent Clinical Progress
Publisher: Springer Science and Business Media LLC
Date: 24-07-2007
DOI: 10.1245/S10434-007-9480-Y
Abstract: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor of low malignant grade characterized by a pattern of slow, infiltrative growth and a marked tendency to recur locally after surgical excision. Wide surgical resection is generally accepted as optimal treatment for DFSP. However, despite optimal surgical management, distant metastases may develop in up to 5% of patients. More than 90% of DFSP are characterized by a reciprocal chromosomal translocation, t(17 ). This rearrangement leads to constitutive activation of the platelet-derived growth factor receptor (PDGFR) as a result of deregulated ligand expression, thus providing a rationale for targeted inhibition of PDGFR as a treatment strategy for patients with unresectable locally advanced or metastatic DFSP. This article reviews the current understanding of DFSP, with emphasis on molecular-level pathogenetic events and their implications for management, and evidence for the role of tyrosine kinase inhibition in improving the outcomes of patients with unresectable locally advanced or metastatic DFSP. Surgery with wide margins remains the cornerstone in the management of DFSP. Recently, imatinib, a potent, selective inhibitor of the PDGFR alpha and PDGFR beta protein-tyrosine kinases, has been reported to induce complete or partial remissions in most patients treated for advanced DFSP. Imatinib is approved for treatment of adult patients with unresectable, recurrent, and/or metastatic DFSP who are not eligible for surgery. Future investigations will determine whether imatinib can also be used in the neoadjuvant setting to reduce tumor volume, thereby allowing resection of very large DFSP that would otherwise not be resectable.
BRAF-targeted therapy and immune responses to melanoma
Publisher: Informa UK Limited
Date: 06-2013
DOI: 10.4161/ONCI.24462
Correlation of Ataxia-Telangiectasia-Mutated (ATM) gene loss with outcome in head and neck squamous cell carcinoma.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.ORALONCOLOGY.2012.02.014
Abstract: Ataxia-Telangiectasia-Mutated (ATM) gene loss has been associated with poor prognosis and treatment resistance in head and neck squamous cell carcinomas (HNSCC). We investigated the relationship between ATM loss detected by fluorescence in-situ hybridisation (FISH) with patient outcome, and its relationship with Human Papillomavirus (HPV) 16(INK4A) status. Copy number of the ATM gene and chromosome 11 were determined by FISH and HPV status was determined using p16(INK4A) immunohistochemistry in 87 paraffin embedded tumour s les from patients with HNSCC treated with chemoradiation at a single institution. ATM loss was correlated with patient outcome as both a continuous and dichotomous variable. Of 73 evaluable patients, 44 (60.3%) demonstrated loss of the ATM gene. There was no correlation between ATM loss (defined as a mean ratio of ATM: chromosome 11 2.5 copies of chromosome 11) which was significantly associated with p16(INK4A) negative status (p=0.0004), but did not influence outcome. ATM loss is a frequent event in HNSCC, however it does not impact outcome after treatment with chemoradiation. Polysomy of chromosome 11 was significantly associated with p16(INK4A) negative status but also lacks prognostic significance.
A community-based model of rapid autopsy in end-stage cancer patients.
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NBT.3674
Correlation of p16 status, hypoxic imaging using [18F]-misonidazole positron emission tomography and outcome in patients with loco-regionally advanced head and neck cancer.
Publisher: Wiley
Date: 02-2014
Abstract: We investigated the relationship between hypoxia, human papillomavirus (HPV) status and outcome in head and neck squamous cell carcinoma. Patients with stage III and IV head and neck squamous cell carcinoma treated on phase I and II chemoradiation trials with 70-Gy radiation combined with tirapazamine/cisplatin or cisplatin/fluorouracil (5FU), hypoxic imaging using [18F]-misonidazole positron emission tomography and known HPV status (by p16 immunohistochemistry) were included in this sub-study. Separate analyses were conducted to consider the impact of tirapazamine on HPV-negative tumours in the phase II trial. Both p16-positive oropharyngeal tumours and p16-negative head and neck squamous cell carcinoma tumours had a high prevalence of tumour hypoxia 14/19 (74%) and 35/44 (80%), respectively. The distribution of hypoxia (primary, nodal) was similar. On phase II, trial patients with p16-negative hypoxic tumours had worse loco-regional control with cisplatin and 5FU compared with tirapazamine and cisplatin (P < 0.001) and worse failure-free survival (hazard ratio = 5.18 95% confidence interval, 1.98-13.55 P = 0.001). Only 1 out of 14 p16-positive patients on the phase II trial experienced loco-regional failure. Hypoxia, as assessed by [18F]-misonidazole positron emission tomography, is frequently present in both p16-positive and negative head and neck cancer. Further research is required to determine whether hypoxic imaging can be used to predict benefit from hypoxia-targeting therapies in patients with p16-negative tumours.
Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation
Publisher: American Society of Hematology
Date: 15-09-2008
DOI: 10.1182/BLOOD-2007-09-111856
Abstract: c-MYC inhibits differentiation and regulates the process by which cells acquire biomass, cell growth. Down-regulation of c-MYC, reduced cell growth, and decreased activity of the PI3K/AKT/mTORC1 signal transduction pathway are features of the terminal differentiation of committed myeloid precursors to polymorphonuclear neutrophils. Since mTORC1 regulates growth, we hypothesized that pharmacological inhibition of mTORC1 by rapamycin may reverse the phenotypic effects of c-MYC. Here we show that granulocytes blocked in their ability to differentiate by enforced expression of c-MYC can be induced to differentiate by reducing exogenous c-MYC expression through rapamycin treatment. Rapamycin also reduced expression of endogenous c-MYC and resulted in enhanced retinoid-induced differentiation. Total cellular c-Myc mRNA and c-MYC protein stability were unchanged by rapamycin, however the amount of c-Myc mRNA associated with polysomes was reduced. Therefore rapamycin limited expression of c-MYC by inhibiting c-Myc mRNA translation. These findings suggest that mTORC1 could be targeted to promote terminal differentiation in myeloid malignancies characterized by dysregulated expression of c-MYC.
Targeting metabolic reprogramming as a potential therapeutic strategy in melanoma
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.PHRS.2016.02.009
Abstract: Metabolic reprogramming is a recognized hallmark of cancer. In order to support continued proliferation and growth, tumor cells must metabolically adapt to balance their bioenergetic and biosynthetic needs. To achieve this, cancer cells switch from mitochondrial oxidative phosphorylation to predominantly rely on glycolysis, a process known as the "Warburg effect". The BRAF oncogene has recently emerged as a critical regulator of this process in melanoma, bringing to the fore the importance of metabolic reprogramming in the pathogenesis and treatment of metastatic melanoma. In this review, we summarize our current understanding of oncogenic reprogramming of metabolism in BRAF and NRAS mutant melanoma, and highlight emerging evidence supporting a metabolic basis for MAPK pathway inhibitor resistance and metabolic vulnerabilities that may be exploited to overcome this.
Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2017
DOI: 10.1158/1078-0432.CCR-17-0172
Abstract: Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. Experimental Design: Gene expression of archival tumor s les from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P & 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures. Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8 95% confidence interval (CI), 1.3–2.6, P = 0.0001] and in the coBRIM validation set (n = 101 HR, 1.6 95% CI, 1.0–2.5 P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99 HR, 1.1 95% CI, 0.7–1.8 P = 0.66). Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res 23(17) 5238–45. ©2017 AACR.
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486667.V1
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Melanoma
Publisher: Springer Science and Business Media LLC
Date: 23-04-2015
DOI: 10.1038/NRDP.2015.3
Abstract: Melanoma is a common cancer in the Western world with an increasing incidence. Sun exposure is still considered to be the major risk factor for melanoma. The prognosis of patients with malignant (advanced-stage) melanoma differs widely between countries, but public c aigns advocating early detection have led to significant reductions in mortality rates. As well as sun exposure, distinct genetic alterations have been identified as associated with melanoma. For ex le, families with melanoma who have germline mutations in CDKN2A are well known, whereas the vast majority of sporadic melanomas have mutations in the mitogen-activated protein kinase cascade, which is the pathway with the highest oncogenic and therapeutic relevance for this disease. BRAF and NRAS mutations are typically found in cutaneous melanomas, whereas KIT mutations are predominantly observed in mucosal and acral melanomas. GNAQ and GNA11 mutations prevail in uveal melanomas. Additionally, the PI3K-AKT-PTEN pathway and the immune checkpoint pathways are important. The finding that programmed cell death protein 1 ligand 1 (PDL1) and PDL2 are expressed by melanoma cells, T cells, B cells and natural killer cells led to the recent development of programmed cell death protein 1 (PD1)-specific antibodies (for ex le, nivolumab and pembrolizumab). Alongside other new drugs - namely, BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib and cobimetinib) - these agents are very promising and have been shown to significantly improve prognosis for patients with advanced-stage metastatic disease. Early signs are apparent that these new treatment modalities are also improving long-term clinical benefit and the quality of life of patients. This Primer summarizes the current understanding of melanoma, from mechanistic insights to clinical progress. For an illustrated summary of this Primer, visit: X2N9s.
Association of programmed death ligand‐1 (PD‐L1) expression with treatment outcomes in patients with BRAF mutation‐positive melanoma treated with vemurafenib or cobimetinib combined
Publisher: Wiley
Date: 10-12-2017
DOI: 10.1111/PCMR.12670
Abstract: The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1
Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K
Publisher: Elsevier BV
Date: 12-2010
A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner
Publisher: Impact Journals, LLC
Date: 19-07-2016
Clinical and biological efficacy of recombinant human interleukin-21 in patients with stage IV malignant melanoma without prior treatment: a phase IIa trial.
Publisher: American Association for Cancer Research (AACR)
Date: 15-03-2009
DOI: 10.1158/1078-0432.CCR-08-2663
Abstract: Purpose: Human interleukin-21 (IL-21) is a class I cytokine that mediates activation of CD8+ T cells, natural killer (NK) cells, and other cell types. We report final clinical and biological results of a phase II study of recombinant human IL-21 (rIL-21) in patients with metastatic melanoma. Experimental Design: Open-label, single-arm, two-stage trial. Eligibility criteria: unresectable metastatic melanoma, measurable disease by Response Evaluation Criteria in Solid Tumors, no prior systemic therapy (adjuvant IFN permitted), adequate major organ function, good performance status, no significant autoimmune disease, and life expectancy at least 4 months. Primary objective: antitumor efficacy (response rate). Secondary objectives: safety, blood biomarkers, and generation of anti-rIL-21 antibodies. rIL-21 (30 μg/kg/dose) was administered by intravenous bolus injection in 8-week cycles (5 dosing days followed by 9 days of rest for 6 weeks and then 2 weeks off treatment). Results: Stage I of the study comprised 14 patients. One confirmed complete response (CR) was observed, and as per protocol, 10 more patients were accrued to stage II (total n = 24: 10 female and 14 male). Best tumor response included one confirmed CR and one confirmed partial response, both with lung metastases. Treatment was overall well tolerated. Biomarker analyses showed increases in serum soluble CD25, frequencies of CD25+ NK and CD8+ T cells, and mRNA for IFN-γ, perforin, and granzyme B in CD8+ T and NK cells. Conclusions: rIL-21 administered at 30 μg/kg/d in 5-day cycles every second week is biologically active and well tolerated in patients with metastatic melanoma. Confirmed responses, including one CR, were observed.
Supplementary Table S1 from Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543848.V1
Abstract: Supplementary Table S1
IL-21 induces in vivo immune activation of NK cells and CD8+ T cells in patients with metastatic melanoma and renal cell carcinoma
Publisher: Springer Science and Business Media LLC
Date: 20-02-2008
Health Care Resource Utilization and Associated Costs Among Metastatic Cutaneous Melanoma Patients Treated with Ipilimumab (INTUITION Study)
Publisher: Oxford University Press (OUP)
Date: 19-05-2017
DOI: 10.1634/THEONCOLOGIST.2016-0272
Abstract: There are limited real-world data on health care resource utilization (HCRU) among advanced melanoma patients. The objective of this study was to describe HCRU and health care costs associated with the management of advanced melanoma patients receiving ipilimumab. This retrospective multinational, observational study included advanced melanoma patients from Australia, Germany, Italy, and Spain who had received at least 1 dose of ipilimumab. Data extracted from medical charts included inpatient admissions, outpatient visits, surgical procedures, laboratory investigations, radiation therapy, imaging studies, and concomitant medications. Cost estimates were based on unit costs from country-specific standard reimbursement sources. Subgroup analyses were performed for BRAF mutation status and ipilimumab refractory patients, who had disease progression within 24 weeks of their last dose of ipilimumab. Mean age of 362 enrolled patients was 60.6 years (standard deviation [SD] 14.4). During a median follow-up period of 30.2 weeks, 57% of patients were admitted to hospital and 16% underwent surgery. Health care resource utilization rates varied substantially across countries and were highest in Germany. Concomitant medications to treat adverse events were commonly used. Subgroup analyses showed higher utilization rates among ipilimumab refractory and BRAF mutant patients. Mean weekly total costs associated with HCRU were lower in the pre-progression period (€107 95% confidence interval (CI): 79–145) than in the post-progression period (€216 95% CI: 180–259). Health care resource utilization pattern and associated costs among patients treated with ipilimumab varied greatly among countries and between pre- and post-progression periods. There is a high economic burden associated with ipilimumab refractory melanoma.
Inhibition of Mutated, Activated BRAF in Metastatic Melanoma
Publisher: Massachusetts Medical Society
Date: 26-08-2010
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486673.V1
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT.
Publisher: Springer Science and Business Media LLC
Date: 04-2010
Decline in cancer pathology notifications during the 2020 COVID‐19‐related restrictions in Victoria
Publisher: AMPCo
Date: 24-02-2021
DOI: 10.5694/MJA2.50968
Preclinical Evaluation of Nilotinib Efficacy in an Imatinib-Resistant KIT-Driven Tumor Model
Publisher: American Association for Cancer Research (AACR)
Date: 05-2010
DOI: 10.1158/1535-7163.MCT-09-1181
Abstract: The novel KIT inhibitor nilotinib is currently being evaluated for its clinical utility in the treatment of gastrointestinal stromal tumor. However, the effects of nilotinib in cells expressing commonly occurring KIT mutations remain to be fully defined. The aim of this study was therefore to investigate the efficacy of nilotinib against cells expressing imatinib-sensitive or imatinib-resistant KIT mutations and to evaluate [18F] fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging as a biomarker of nilotinib response in vivo. Nilotinib inhibited the proliferation of imatinib-responsive V560G-KIT FDC-P1 and imatinib-resistant D816V-KIT FDC-P1 cells with a GI50 of 4.9 and 630 nmol/L, respectively, whereas apoptosis studies revealed that nilotinib and imatinib were equipotent against the V560G cell line. In contrast, although 10 μmol/L nilotinib induced & % apoptosis in the D816V cells at 16 hours, 10 μmol/L imatinib had no effect on cell survival at 24 hours. Syngeneic DBA2/J mice bearing FDC-P1-KIT tumors were evaluated for response to nilotinib by FDG-PET. V560G-KIT FDC-P1 tumor FDG uptake was significantly reduced compared with baseline levels following 2 days of nilotinib treatment. In contrast, no effect of nilotinib was observed on tumor growth or FDG-PET uptake into D816V tumors despite intratumoral drug levels reaching in excess of 10 μmol/L at 4 hours after dosing. Biomarker analysis revealed the inhibition of KIT phosphorylation in V560G but not D816V tumors. These findings show the in vivo activity of nilotinib in the treatment of tumors bearing V560G-KIT but not D816V-KIT and the utility of FDG-PET imaging to assess tumor response to this agent. Mol Cancer Ther 9(5) 1461–8. ©2010 AACR.
An inverse stage-shift model to estimate the excess mortality and health economic impact of delayed access to cancer services due to the COVID-19 pandemic
Publisher: Cold Spring Harbor Laboratory
Date: 30-05-2020
DOI: 10.1101/2020.05.30.20117630
Abstract: Decreased cancer incidence and reported changes to clinical management indicate that the COVID-19 pandemic will result in diagnostic and treatment delays for cancer patients. We aimed to develop a flexible model to estimate the impact of delayed diagnosis and treatment initiation on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation. The stage-shift model estimates population-level health economic outcomes by weighting disease stage-specific outcomes by the distribution of stages at treatment initiation, assuming delays lead to stage-progression. It allows for extrapolation of population-level survival data using parametric distributions to calculate the expected survival in life years. The model was demonstrated based on an analysis of the impact of 3 and 6-month delays for stage I breast cancer, colorectal cancer and lung cancer patients, and for T1 melanoma, based on Australian data. In the absence of patient-level data about time to stage progression, two approaches were explored to estimate the proportion of patients that would experience a stage shift following the delay: 1) based on the relation between time to treatment initiation and overall survival (breast, colorectal and lung cancer), and 2) based on the tumour growth rate (melanoma). The model is available on stage-shift.personex.nl/ . A shift from stage I to stage II due to a 6-month delay is least likely for colorectal cancer patients, with an estimated proportion of 3% of the stage I patients diagnosed in 2020 progressing to stage II, resulting in 11 excess deaths after 5 years and a total of 96 life years lost over a 10-year time horizon. For breast and lung cancer, progression from stage I to stage II due to a 6-month delay were slightly higher at 5% (breast cancer) and 8% (lung cancer), resulting in 25 and 43 excess deaths after 5 years, and 239 and 373 life years lost over a 10-year time horizon, respectively. For melanoma, with 32% of T1 patients progressing to T2 disease following a 6-month delay, the model estimated 270 excess death after 5 years and 2584 life years lost over a 10-year time horizon. Using a conservative 3-month delay in diagnosis and treatment initiation due to the COVID-19 pandemic, this study predicts nearly 90 excess deaths and $12 million excess healthcare costs in Australia over 5 years for the in 2020 diagnosed patients for 4 cancers. If the delays increase to 6 months, excess mortality and cost approach nearly 350 deaths and $46 million in Australia. More accurate data on stage of disease during and after the COVID-19 pandemic are critical to obtain more reliable estimates.
Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance
Publisher: Wiley
Date: 03-01-2018
DOI: 10.1002/IJC.31220
Abstract: Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination was assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors. Xenograft studies were then performed to test the in vivo efficacy of the BRAF and CDK4/6 inhibitor combination. Melanoma cells that had developed early reversible tolerance or acquired resistance to BRAF inhibition remained sensitive to palbociclib. In drug‐tolerant cells, the efficacy of the combination of palbociclib with BRAF and/or MEK inhibitors was equivalent to single agent palbociclib. Similarly, acquired BRAF inhibitor resistance cells lost efficacy to the palbociclib and BRAF combination. In contrast, upfront treatment of melanoma cells with palbociclib in combination with BRAF and/or MEK inhibitors induced either cell death or senescence and was superior to a BRAF plus MEK inhibitor combination. In vivo palbociclib plus BRAF inhibitor induced rapid and sustained tumor regression without the development of therapy resistance. In summary, upfront dual targeting of CDK4/6 and mutant BRAF signaling enables tumor cells to evade resistance to monotherapy and is required for robust and sustained tumor regression. Melanoma patients whose tumors have acquired resistance to BRAF inhibition are less likely to have favorable responses to subsequent treatment with the triplet combination of BRAF, MEK and CDK4/6 inhibitors.
The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2013
DOI: 10.1158/1078-0432.CCR-13-0259
Abstract: The recent clinical success of targeted therapies in melanoma directed at the oncogene BRAF validates the concept of targeting oncogenes. The p16-cyclin D-CDK4/6-retinoblastoma protein pathway (CDK4 pathway) is dysregulated in 90% of melanomas, and is, therefore, an obvious therapeutic target for this disease. The main outcome of CDK4 activation is the phosphorylation and, thus, inhibition of the retinoblastoma protein leading to G1–S cell-cycle transition. In addition, CDK4 directly phosphorylates other proteins that promote cell-cycle progression and inhibit both cell senescence and apoptosis. In preclinical studies, the response to CDK4 inhibition correlates with genomic changes that increase CDK4 activity, most notably where the tumor suppressor CDKN2A (p16INK4A) is deleted. A central question is whether melanomas with activating events in the CDK4 pathway have become “addicted” to this signaling pathway, in which case inhibition of CDK4 would not simply induce cell-cycle arrest but induce cell death and tumor regression. Recently, a number of selective CDK4/6 inhibitors have entered clinical trials, and these compounds are showing great promise in that they are well tolerated and show clinical benefit. This review discusses the CDK4 pathway, its dysregulation in melanoma, the consequences of CDK4 pathway inhibition, and potential novel combinational strategies for the treatment of melanoma. Clin Cancer Res 19(19) 5320–8. ©2013 AACR.
Tumour mutation status and sites of metastasis in patients with cutaneous melanoma
Publisher: Springer Science and Business Media LLC
Date: 08-08-2017
DOI: 10.1038/BJC.2017.254
Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486691.V1
Abstract: Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
A phase I trial of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2013
DOI: 10.1007/S00280-012-2009-5
Abstract: Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities. Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6-bevacizumab for 12 cycles. Blood s les were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1 400 mg, DL2 600 mg, DL3 800 mg daily. Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2) Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib. MTD was imatinib 400 mg plus full dose mFOLFOX-bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR.
The role of BRAF mutations in primary melanoma growth rate and survival.
Publisher: Oxford University Press (OUP)
Date: 13-06-2015
DOI: 10.1111/BJD.13756
Abstract: The clinical behaviour and prognosis of primary melanomas harbouring BRAF mutations is not fully understood. To investigate the effect of mutation status on primary melanoma growth rate and melanoma-specific survival (MSS). A prospective cohort of 196 patients with stage I-III primary cutaneous melanoma were followed for a median of 92 months, pre-dating the institution of BRAF inhibitor therapy. Clinicopathological variables were correlated with mutation status and hazard ratios (HRs) estimated for MSS. Of 196 tumours, 77 (39.2%) were BRAF V600E, 10 (5.1%) BRAF V600K and 33 (16.8%) were NRAS mutant. BRAF V600E mutant melanomas were associated with favourable clinical characteristics and tended to be slower growing compared with BRAF V600K, NRAS mutant or BRAF/NRAS wild-type tumours (0.12 mm per month, 0.61 mm per month, 0.36 mm per month and 0.23 mm per month, respectively P = 0.05). There were 39 melanoma deaths, and BRAF mutant melanomas were associated with poorer MSS in stage I-III disease [HR 2.60, 95% confidence interval (CI) 1.20-5.63 P = 0.02] and stage I-II disease (HR 3.39, 95% CI 1.12-10.22 P = 0.03) after adjusting for other prognostic variables. Considered separately, BRAF V600E mutant melanomas were strongly associated with MSS independently of thickness and nodal status (HR 3.89, 95% CI 1.67-9.09 P < 0.01) but BRAF V600K mutant tumours were not (HR 1.19, 95% CI 0.36-3.92 P = 0.77). The presence of a BRAF mutation does not necessarily 'drive' more rapid tumour growth but is associated with poorer MSS in patients with early-stage disease.
Review
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2011
Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486685.V1
Abstract: Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Co-targeting Deoxyribonucleic Acid–Dependent Protein Kinase and Poly(Adenosine Diphosphate-Ribose) Polymerase-1 Promotes Accelerated Senescence of Irradiated Cancer Cells
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.IJROBP.2013.10.043
Abstract: To examine the effects of combined blockade of DNA-dependent protein kinase (DNA-PK) and poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) on accelerated senescence in irradiated H460 and A549 non-small cell lung cancer cells. The effects of KU5788 and AG014699 (inhibitors of DNA-PK and PARP-1, respectively) on clonogenic survival, DNA double-strand breaks (DSBs), apoptosis, mitotic catastrophe, and accelerated senescence in irradiated cells were examined in vitro. For in vivo experiments, H460 xenografts established in athymic nude mice were treated with BEZ235 (a DNA-PK, ATM, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor) and AG014699 to determine effects on proliferation, DNA DSBs, and accelerated senescence after radiation. Compared with either inhibitor alone, combination treatment with KU57788 and AG014699 reduced postradiation clonogenic survival and significantly increased persistence of Gamma-H2AX (γH2AX) foci in irradiated H460 and A549 cells. Notably, these effects coincided with the induction of accelerated senescence in irradiated cells as reflected by positive β-galactosidase staining, G2-M cell-cycle arrest, enlarged and flattened cellular morphology, increased p21 expression, and senescence-associated cytokine secretion. In irradiated H460 xenografts, concurrent therapy with BEZ235 and AG014699 resulted in sustained Gamma-H2AX (γH2AX) staining and prominent β-galactosidase activity. Combined DNA-PK and PARP-1 blockade increased tumor cell radiosensitivity and enhanced the prosenescent properties of ionizing radiation in vitro and in vivo. These data provide a rationale for further preclinical and clinical testing of this therapeutic combination.
Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial
Publisher: Elsevier BV
Date: 07-2008
Cell Division and Hematopoietic Stem Cells: Not Always Exhausting
Publisher: Informa UK Limited
Date: 02-05-2005
DOI: 10.4161/CC.4.7.1831
Abstract: Pluripotent hematopoietic stem cells (HSCs) sustain blood cell production throughout an in idual's lifespan through complex processes supported by self-renewal, differentiation, senescence or cell death decisions of the HSCs. These decisions are tightly regulated under homeostatic conditions, allowing both the continuous generation of progenitors and mature cells in addition to the maintenance and replenishment of the HSC pool. Several recent studies have provided insights into some of the key molecular mechanisms regulating these different cell fate decisions. One of the emerging themes of these studies is that of the importance of cell cycle regulators in the maintenance of HSCs.
Supplementary Figures from γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543539.V1
Abstract: Supplementary Figures
MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation
Publisher: Wiley
Date: 29-07-2004
BRAF Inhibition in BRAFV600E-Positive Anaplastic Thyroid Carcinoma.
Publisher: Harborside Press, LLC
Date: 03-2016
Abstract: The efficacy of targeted monotherapy for BRAF(V600E)-positive anaplastic thyroid carcinomas (ATC) is not established. We report 2 cases of BRAF(V600E)-positive ATC treated with a BRAF inhibitor. A 49-year-old woman with a T4bN1bM0 ATC manifested symptomatic metastatic disease 8 weeks after radical chemoradiotherapy. Within 1 month of BRAF inhibitor monotherapy, a complete symptomatic response was observed, with FDG-PET scan confirming metabolic and radiologic response. Treatment was terminated after 3 months because of disease progression. The patient died 11 months after primary diagnosis. A 67-year-old man received first-line BRAF inhibitor for a T4aN1bM0 ATC. Within 10 days of treatment his pain had stabilized and his tumor had clinically halved in size. Stable disease was achieved for 11 weeks but the patient died 11 months after diagnosis because of disease progression. BRAF inhibitor monotherapy in ATC may obtain clinical benefit of short duration. Upfront combination therapy should be investigated in this patient subgroup.
Supplementary Figures from CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540163.V1
Abstract: Supplementary Figures 1-12
Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases
Publisher: Springer Science and Business Media LLC
Date: 18-05-2017
DOI: 10.1038/BJC.2017.142
Data from CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.C.6549299.V1
Abstract: Abstract Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor–positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic, and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunologic T-cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous antitumor T-cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor T cells, and induced a retinoblastoma-dependent T-cell phenotype supportive of favorable responses to immune checkpoint blockade in patients with melanoma. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost antitumor T-cell immunity. Significance: Immunologic memory is critical for sustained antitumor immunity. Our discovery that CDK4/6 inhibitors drive T-cell memory fate commitment sheds new light on their clinical activity, which is essential for the design of clinical trial protocols incorporating these agents, particularly in combination with immunotherapy, for the treatment of cancer. i This article is highlighted in the In This Issue feature, p. 2355 /i /
Clinicopathological characteristics associated with BRAF(K601E) and BRAF(L597) mutations in melanoma.
Publisher: Wiley
Date: 17-01-2016
DOI: 10.1111/PCMR.12450
Abstract: BRAF mutations at codons L597 and K601 occur uncommonly in melanoma. Clinical and pathological associations of these mutations were investigated in a cohort of 1119 patients with known BRAF mutation status. A BRAF mutation was identified in 435 patients Mutations at L597 and the K601E mutation were seen in 3.4 and 3.2% of these, respectively. K601E melanomas tended to occur in male patients, a median age of 58 yr, were generally found on the trunk (64%) and uncommonly associated with chronically sun-damaged (CSD) skin. BRAF L597 melanomas occurred in older patients (median 66 yr), but were associated with CSD skin (extremities or head and neck location - 73.3%, P = 0.001). Twenty-three percent of patients with V600E- and 43% of patients with K601E-mutant melanomas presented with nodal disease at diagnosis compared to just 14% of patients with BRAF wild-type tumors (P = 0.001 and 0.006, respectively). Overall, these mutations represent a significant minority of BRAF mutations, but have distinct clinicopathological phenotypes and clinical behaviors.
Data from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532370
Abstract: AbstractPurpose: OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG sub /sub monoclonal anti-OX40 antibody. Patients and Methods: Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2–1,200 mg i n /i = 34) was followed by expansion cohorts at 300 mg ( i n /i = 138) for patients with melanoma, renal cell carcinoma, non–small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer. Results: MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE) 56% of AEs, mostly grade 1–2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease. Conclusions: Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists. /
Combination Therapies to Inhibit the RAF/MEK/ERK Pathway in Melanoma: We are not Done Yet
Publisher: Frontiers Media SA
Date: 17-07-2015
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma
Publisher: Springer Science and Business Media LLC
Date: 09-2010
DOI: 10.1038/NATURE09454
Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 14-09-2017
DOI: 10.1158/1078-0432.CCR-16-2923
Abstract: Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated BRAF-mutant melanoma. Experimental Design: The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50–700 mg) or twice-daily (75–150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib. Results: Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF V600E–mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar–plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months [95% confidence interval (CI), 7.4–not reached (NR)]. In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9–3.7). Conclusions: Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. Clin Cancer Res 23(18) 5339–48. ©2017 AACR.
Glucocorticoids did not reverse type 1 diabetes mellitus secondary to pembrolizumab in a patient with metastatic melanoma.
Publisher: BMJ
Date: 23-11-2016
c-Myb is required for progenitor cell homeostasis in colonic crypts
Publisher: Proceedings of the National Academy of Sciences
Date: 06-03-2007
Abstract: The colonic crypt is the functional unit of the colon mucosa with a central role in ion and water reabsorption. Under steady-state conditions, the distal colonic crypt harbors a single stem cell at its base that gives rise to highly proliferative progenitor cells that differentiate into columnar, goblet, and endocrine cells. The role of c-Myb in crypt homeostasis has not been elucidated. Here we have studied three genetically distinct hypomorphic c-myb mutant mouse strains, all of which show reduced colonic crypt size. The mutations target the key domains of the transcription factor: the DNA binding, transactivation, and negative regulatory domains. In vivo proliferation and cell cycle marker studies suggest that these mice have a progenitor cell proliferation defect mediated in part by reduced Cyclin E1 expression. To independently assess the extent to which c-myb is required for colonic crypt homeostasis we also generated a novel tissue-specific mouse model to allow the deletion of c-myb in adult colon, and using these mice we show that c-Myb is required for crypt integrity, normal differentiation, and steady-state proliferation.
An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice
Publisher: American Society for Clinical Investigation
Date: 02-2012
DOI: 10.1172/JCI59309
Prospective Comparison of T1-SPACE and MPRAGE for the Identification of Intrinsic T1 Hyperintensity in Patients with Intracranial Melanoma Metastases
Publisher: American Society of Neuroradiology (ASNR)
Date: 24-08-2023
DOI: 10.3174/AJNR.A7975
Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486679.V1
Abstract: Supplementary Table from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy
Publisher: Springer Science and Business Media LLC
Date: 28-04-2016
DOI: 10.1038/BJC.2016.107
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Publisher: Massachusetts Medical Society
Date: 05-10-2017
18F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model
Publisher: Society of Nuclear Medicine
Date: 16-09-2010
DOI: 10.2967/JNUMED.109.073288
Abstract: Targeting the mammalian target of rapamycin (mTOR) pathway is a potential means of overcoming cisplatin resistance in ovarian cancer patients. Because mTOR inhibition affects cell proliferation, we aimed to study whether 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET could be useful for monitoring early response to treatment with mTOR inhibitors in an animal model of cisplatin-resistant ovarian tumor. BALB/c nude mice bearing subcutaneous human SKOV3 ovarian cancer xenografts were treated with either the mTOR inhibitor everolimus (5 mg/kg) or vehicle, and (18)F-FLT PET was performed at baseline, day 2, and day 7 of treatment. (18)F-FLT uptake was evaluated by calculation of mean standardized uptake value (SUVmean) corrected for partial-volume effect. Ex vivo immunohistochemistry studies were performed on separate cohorts of mice treated as above and sacrificed at the same time points as for the PET studies. The ex vivo analysis included bromodeoxyuridine incorporation as a marker of cell proliferation, and phosphorylation of ribosomal protein S6 as a downstream marker of mTOR activation. During the treatment period, no significant change in tumor (18)F-FLT uptake was observed in the vehicle group, whereas in everolimus-treated mice, (18)F-FLT SUVmean decreased by 33% (P = 0.003) at day 2 and 66% (P < 0.001) at day 7, compared with baseline. Notably, the reduction of (18)F-FLT uptake observed at day 2 in the everolimus group preceded changes in tumor volume, and a significant difference in (18)F-FLT uptake was observed between vehicle and drug-treated tumors at both day 2 (P = 0.0008) and day 7 (P = 0.01). In ex vivo studies, everolimus treatment resulted in a 98% reduction in phosphorylated ribosomal protein S6 immunostaining at day 2 (P = 0.02) and 91% reduction at day 7 (P = 0.003), compared with the vehicle group. Bromodeoxyuridine incorporation was reduced by 65% at day 2 (not significant) and by 41% at day 7 (P = 0.02) in drug versus vehicle groups. Reduction in (18)F-FLT uptake correlates well with the level of mTOR inhibition by everolimus in the SKOV3 ovarian tumor model. These data suggest that early treatment monitoring by (18)F-FLT PET may be of use in future preclinical or clinical trials evaluating treatment of cisplatin-resistant ovarian tumors by mTOR inhibitors.
Safety and efficacy of combining ATRA with G-CSF in HSPC mobilization; a pilot study in multiple myeloma and non-Hodgkin's lymphoma patients
Publisher: Springer Science and Business Media LLC
Date: 06-08-2007
Relationship between Epidermal Growth Factor Receptor Status, p16INK4A, and Outcome in Head and Neck Squamous Cell Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 06-2011
DOI: 10.1158/1055-9965.EPI-10-1262
Abstract: Background: Human papilloma virus (HPV) infection is a powerful prognostic biomarker in head and neck squamous cell carcinoma (HNSCC). Increased epidermal growth factor receptor (EGFR) gene copy number and protein expression have been reported to be negative predictors of outcome. This study examined the relationship between HPV status, EGFR gene copy number, EGFR protein expression, and clinical outcome in HNSCC patients treated with chemoradiation. Methods: HPV status was determined using p16INK4A immunohistochemistry (IHC), EGFR gene copy number was evaluated with FISH, and EGFR protein expression by IHC in 212 subjects. Results: EGFR FISH was positive in 41 of 204 (20%) patients and was negatively correlated with failure-free survival (FFS HR = 1.84, P = 0.027) and overall survival (OS HR = 1.78, P = 0.082). For p16INK4A, 85 of 200 (42.5%) patients were found to be p16 positive, including 75 of 131 (57%) with oropharyngeal cancer. Patients with p16-positive oropharyngeal cancer had significantly improved FFS (HR = 0.28, P & 0.001) and OS (HR = 0.31, P = 0.002). Only 2 of 126 (1.6%) oropharyngeal cancer patients were found to be p16+/EGFR FISH+. EGFR IHC was positive in 81 of 93 (87%) of patients and was associated with poorer FFS (HR = 1.98, P = 0.35) and OS (HR = 2.52, P = 0.22). Conclusions: Increased EGFR gene copy number is largely restricted to p16INK4A-negative oropharyngeal cancer. Although p16INK4A and EGFR FISH are both predictive of outcome in univariate analyses, only p16INK4A remains independently predictive. Impact: Knowledge of HPV and EGFR status can have implications for treatment options and prognosis in HNSCC. Cancer Epidemiol Biomarkers Prev 20(6) 1230–7. ©2011 AACR.
Data from Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550431.V1
Abstract: Abstract Combined inhibition of BRAF, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a i BRAF sup V600 /sup /i mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic i Braf sup V600E /sup Cdkn2a sup −/− /sup Pten sup −/− /sup /i melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA sequencing analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted proinflammatory macrophages and cross-priming CD103 sup + /sup dendritic cells, the absence of which correlated with poor overall survival and clinical responses to ICB in patients with melanoma. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses i ex vivo /i . While combined BRAF, MEK, and CDK4/6 inhibition demonstrates favorable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact antitumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRAF, MEK, and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma. /
Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging
Publisher: American Association for Cancer Research (AACR)
Date: 09-2005
DOI: 10.1158/1535-7163.MCT-05-0066
Abstract: Blockade of signaling through the epidermal growth factor receptor (EGFR) tyrosine kinase by inhibitors such as gefitinib (Iressa) can inhibit tumor angiogenesis and enhance responses to ionizing radiation. In this study, the ability of gefitinib to modulate intratumoral oxygenation was evaluated in human EGFR-expressing A431 squamous cell carcinoma xenografts using in vivo small animal positron emission tomography (PET) imaging with the hypoxia marker [18F]fluoroazomycin arabinoside (FAZA) and by the immunohistochemical detection of hypoxia-induced adducts of the 2-nitroimidazole, pimonidazole. Serial noninvasive PET imaging of A431 xenografts showed a significant reduction in FAZA uptake following treatment with 75 mg/kg/d of gefitinib [tumor to background ratio, 6.1 ± 1.0 (pretreatment) versus 2.3 ± 0.6 (posttreatment) P = 0.0004]. Similarly, ex vivo quantitation of FAZA uptake showed significantly reduced FAZA uptake in established A431 xenografts treated with gefitinib compared with vehicle control (tumor to blood ratio for controls versus gefitinib, 8.0 ± 3.0 versus 2.7 ± 0.8 P = 0.007 or tumor to muscle ratio controls versus gefitinib, 8.6 ± 2.8 versus 2.6 ± 1.0 P = 0.002). The effect of gefitinib treatment seemed to be independent of tumor size. In addition, gefitinib treatment reduced pimonidazole-binding in A431 xenografts measured after 5 and 8 days of gefitinib treatment compared with baseline and with tumors treated with vehicle alone. A strong correlation was observed between pimonidazole binding and FAZA uptake. Together, these findings show that gefitinib reduces intratumoral hypoxia.
Data from A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in <i>BRAF</i> V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Com
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6533113
Abstract: AbstractPurpose: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. Patients and Methods: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Results: Thirty-two patients with i BRAF /i V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal i KRAS /i , i NRAS /i , and i MAP2K1 /i mutations, and i MET /i lification. Conclusions: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance. /
Negative cell-cycle regulators cooperatively control self-renewal and differentiation of haematopoietic stem cells
Publisher: Springer Science and Business Media LLC
Date: 16-01-2005
DOI: 10.1038/NCB1214
Abstract: Haematopoietic stem cells (HSCs) are capable of shifting from a state of relative quiescence under homeostatic conditions to rapid proliferation under conditions of stress. The mechanisms that regulate the relative quiescence of stem cells and its association with self-renewal are unclear, as is the contribution of molecular regulators of the cell cycle to these decisions. Understanding the mechanisms that govern these transitions will provide important insights into cell-cycle regulation of HSCs and possible therapeutic approaches to expand HSCs. We have investigated the role of two negative regulators of the cell cycle, p27(Kip1) and MAD1, in controlling this transition. Here we show that Mad1(-/-)p27(Kip1-/-) bone marrow has a 5.7-fold increase in the frequency of stem cells, and surprisingly, an expanded pool of quiescent HSCs. However, Mad1(-/-)p27(Kip1-/-) stem cells exhibit an enhanced proliferative response under conditions of stress, such as cytokine stimulation in vitro and regeneration of the haematopoietic system after ablation in vivo. Together these data demonstrate that the MYC-antagonist MAD1 and cyclin-dependent kinase inhibitor p27(Kip1) cooperate to regulate the self-renewal and differentiation of HSCs in a context-dependent manner.
Erratum: Host immunity contributes to the anti-melanoma activity of BRAF inhibitors (American Society for Clinical Investigation (2013) 123:3 (1371-1381) DOI 10.1172/JCI66236)
Publisher: American Society for Clinical Investigation
Date: 23-11-2016
DOI: 10.1172/JCI84828
The use of ipilimumab in patients with rheumatoid arthritis and metastatic melanoma
Publisher: Elsevier BV
Date: 06-2016
In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 08-2011
DOI: 10.1158/1535-7163.MCT-11-0240
Abstract: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is commonly dysregulated in human cancer, making it an attractive target for novel anticancer therapeutics. We have used a mouse model of ovarian cancer generated by KrasG12D activation and Pten deletion in the ovarian surface epithelium for the preclinical assessment of a novel PI3K/mTOR inhibitor PF-04691502. To enable higher throughput studies, we developed an orthotopic primary transplant model from these mice and evaluated therapeutic response to PF-04691502 using small-animal ultrasound and FDG-PET imaging. PF-04691502 inhibited tumor growth at 7 days by 72% ± 9. FDG-PET imaging revealed that PF-04691502 reduced glucose metabolism dramatically, suggesting FDG-PET may be exploited as an imaging biomarker of target inhibition by PF-04691502. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), were also dramatically inhibited following PF-04691502 treatment. However, as a single agent, PF-04691502 did not induce tumor regression and the long-term efficacy was limited, with tumor proliferation continuing in the presence of drug treatment. We hypothesized that tumor progression was because of concomitant activation of the mitogen-activated protein kinase pathway downstream of KrasG12D expression promoting cell survival and that the therapeutic effect of PF-04691502 would be enhanced by combinatory inhibition of MEK using PD-0325901. This combination induced striking tumor regression, apoptosis associated with upregulation of Bim and downregulation of Mcl-1, and greatly improved duration of survival. These data suggest that contemporaneous MEK inhibition enhances the cytotoxicity associated with abrogation of PI3K/mTOR signaling, converting tumor growth inhibition to tumor regression in a mouse model of ovarian cancer driven by PTEN loss and mutant K-Ras. Mol Cancer Ther 10(8) 1440–9. ©2011 AACR.
BRAF, a target in melanoma
Publisher: Wiley
Date: 13-07-2010
DOI: 10.1002/CNCR.25261
Abstract: The successful translation of therapies targeting signal-transduction pathways that are activated by oncogenes has provided a model for molecularly targeted therapy, and the identification of mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF), a serine/threonine kinase, has turned the attention of the melanoma field toward this concept. The current review indicated that BRAF represents an important target in cancer, in part because it is present in 7% of all cancers and also because it represents the first intracellular signaling molecule that is activated by point mutations for which single-agent therapy appears to have efficacy. Therapy for advanced melanoma has progressed slowly over the past 3 decades, although significant advances have been made in other cancers with the application of cytotoxic chemotherapy and targeted therapies. However, in melanoma, cytotoxic chemotherapies have severe limits, chemotherapy does not convincingly improve on the natural history of metastatic disease and has no role in the adjuvant setting, and cytokine therapy may have a niche in both the adjuvant and metastatic settings but confers only a modest benefit to a small proportion of patients at the cost of severe toxicity. Thus, there are few other cancers in which completely novel therapies are so highly prioritized in clinical research. Understanding network of signal-transduction pathways and how that network may adapt to BRAF inhibition or mitogen-activated protein kinase kinase inhibition will point to the next generation of clinical trials investigating rational combination regimens. The current investigations in melanoma will create a set of hypotheses to be tested in each cancer that harbors BRAF mutations.
Applications of Positron Emission Tomography in the Development of Molecular Targeted Cancer Therapeutics
Publisher: Springer Science and Business Media LLC
Date: 2003
DOI: 10.2165/00063030-200317050-00004
Abstract: For molecular targeted cancer therapies to fulfill their promise in cancer treatment, innovative approaches are required to overcome significant obstacles that exist in the clinical development of these agents. Positron emission tomography (PET) is a functional imaging technology that allows rapid, repeated, noninvasive, in vivo assessment and quantification of many biological processes and in some cases molecular pathways targeted by these therapies. It is highly sensitive, with the capacity to detect subnanomolar concentrations of radiotracer and provides superior image resolution to conventional nuclear medicine imaging with gamma cameras. Novel PET radiotracers have been developed that allow visualisation of a variety of processes including tumour metabolism, cell proliferation, apoptosis, hypoxia and blood flow. Furthermore, specific molecular targets including cellular receptors can be identified using radiolabelled receptor ligands or specific monoclonal antibodies. Improvements in imaging technology leading to the development of small-animal PET scanners, with resolution capable of imaging commonly used mouse models of cancer, will enable PET to play an important role in preclinical proof-of-principle drug studies. Such improvements will also facilitate the validation of imaging protocols that can be readily translated to studies in humans. The greatest utility of PET in the development of molecular targeted therapeutics, however, lies in clinical studies, where PET may play a valuable role in a number of situations. These include selection of patients for therapy through noninvasive identification of the presence of specific molecular targets, pharmacokinetic studies with labelled drugs and pharmacodynamic evaluations of biological parameters to select the optimal biological dose, and assessment of response to therapies.
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