ORCID Profile
0000-0003-1071-7956
Current Organisations
Sir Charles Gairdner Hospital
,
Linear Clinical Research
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Publisher: Springer Science and Business Media LLC
Date: 04-02-2019
DOI: 10.1038/S41598-018-37883-Y
Abstract: Both targeted therapy and immunotherapy have been used successfully to treat melanoma, but the development of resistance and poor response rates to the in idual therapies has limited their success. Designing rational combinations of targeted therapy and immunotherapy may overcome these obstacles, but requires assessment in preclinical models with the capacity to respond to both therapeutic classes. Herein, we describe the development and characterization of a novel, immunogenic variant of the Braf V600E Cdkn2a −/− Pten −/− YUMM1.1 tumor model that expresses the immunogen, ovalbumin (YOVAL1.1). We demonstrate that, unlike parental tumors, YOVAL1.1 tumors are immunogenic in vivo and can be controlled by immunotherapy. Importantly, YOVAL1.1 tumors are sensitive to targeted inhibitors of BRAF V600E and MEK, responding in a manner consistent with human BRAF V600E melanoma. The YOVAL1.1 melanoma model is transplantable, immunogenic and sensitive to clinical therapies, making it a valuable platform to guide strategic development of combined targeted therapy and immunotherapy approaches in BRAF V600E melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424167
Abstract: Figure S1 shows the association of BMP4 expression with tumour aggressiveness and with metastasis-free survival
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.APNR.2017.12.002
Abstract: This study sought to identify clinical, demographic and service-related factors associated with psychological distress amongst outpatient chemotherapy patients. Distress in cancer patients leads to increased risk of psychological comorbidity, contributing to sub-optimal treatment adherence and potentially leading to poorer health outcomes. Screening and recognition of distress and risk factors is an important aspect of holistic care within a multidisciplinary team environment. Data were obtained via survey and chart review of ambulatory chemotherapy patients at three public tertiary referral hospitals in Perth, Western Australia. The DASS-21 was used to screen for psychological distress. Regression analyses were used to assess the relationship between distress and a range of cancer, socioeconomic and treatment factors. Patients with a Karnofsky Performance Score≤80 (OR 3.8, 95% CI [1.7, 78.7]) and average waiting time (between oncology outpatient appointment and commencement of chemotherapy infusion) >60min (OR 2.4, 95% CI [1.04, 5.5]) were at increased risk of moderate-severe distress. Patients with a household income between $AU 50-75,000 p.a. had a lower risk of distress compared to <$25,000 p.a. (OR 0.05, 95% CI [0.01, 0.52]). On sub-scale analysis, depression and anxiety contributed more to overall distress than the stress subscales. Performance status, waiting times and household income were key predictors of distress. Findings could assist clinicians to identify higher-risk population subsets that could benefit from targeted screening and additional psychological and social work support. Findings could also assist administrators to consider the contribution of modifiable factors such as waiting times to patient distress.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424146.V1
Abstract: BMP4 expression in human breast cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6511693
Abstract: Abstract Metastasis is the major cause of death in patients with cancer with no therapeutic cure, treatments remain largely palliative. As such, new targets and therapeutic strategies are urgently required. Here, we show that bone morphogenetic protein-4 (BMP4) blocks metastasis in animal models of breast cancer and predicts improved survival in patients. In preclinical models of spontaneous metastasis, BMP4 acted as an autocrine mediator to modulate a range of known metastasis-regulating genes, including i Smad7 /i , via activation of canonical BMP-SMAD signaling. Restored BMP4 expression or therapeutically administered BMP4 protein, blocked metastasis and increased survival by sensitizing cancer cells to anoikis, thereby reducing the number of circulating tumor cells. Gene silencing of i Bmp4 /i or its downstream mediator i Smad7 /i , reversed this phenotype. Administration of recombinant BMP4 markedly reduced spontaneous metastasis to lung and bone. Elevated levels of BMP4 and SMAD7 were prognostic for improved recurrence-free survival and overall survival in patients with breast cancer, indicating the importance of canonical BMP4 signaling in the suppression of metastasis and highlighting new avenues for therapy against metastatic disease. Significance: Targeting the BMP4–SMAD7 signaling axis presents a novel therapeutic strategy to combat metastatic breast cancer, a disease that has had no reduction in patient mortality over 20 years. /
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.BURNS.2008.10.005
Abstract: This study describes the evaluation of a clinical scar scale for our porcine burn scars, which includes scar cosmetic outcome, colour, height and hair, supplemented with reference porcine scar photographs representing each scar outcome and scar colour scores. A total of 72 porcine burn scars at week 6 after burn were rated in vivo and/or on photographs. Good agreements were achieved for both intra-rater reliability (correlation is 0.86-0.98) and inter-rater reliability (ICC=80-85%). The results showed statistically significant correlations for each pair in this clinical scar scale (p<0.01), with the best correlation found between scar cosmetic outcome and scar colour. A multivariate principle components analysis revealed that this clinical scar assessment was highly correlated with scar histology, wound size, and re-epithelialisation data (p<0.001). More severe scars are clinically characterised by darker purple colouration, more elevation, no presence of hair, histologically by thicker scar tissue, thinner remaining normal dermis, are more likely to have worse contraction, and slower re-epithelialisation. This study demonstrates that our clinical scar scale is a reliable, independent and valuable tool for assessing porcine burn outcome and truthfully reflects scar appearance and function. To our knowledge, this is the first study demonstrating a high correlation between clinical scar assessment and scar histology, wound contraction and re-epithelialisation data on porcine burn scars. We believe that the successful use of porcine scar scales is invaluable for assessing potential human burn treatments.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424164
Abstract: Figure S2 shows the effect of BMP4 on the in vitro properties of tumour cells and response of tumours in vivo.
Publisher: Elsevier BV
Date: 05-2023
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543848.V1
Abstract: Supplementary Table S1
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.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424161
Abstract: Figure S3 shows that BMP4 does not alter migration or invasion in vitro and that BMP7 can also inhibit metastasis.
Publisher: MDPI AG
Date: 17-12-2021
Abstract: Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424152.V1
Abstract: Supplementary methods
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424149.V1
Abstract: PCR primers
Publisher: Wiley
Date: 18-04-2018
DOI: 10.1002/PON.4435
Publisher: Proceedings of the National Academy of Sciences
Date: 22-08-2019
Abstract: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5–MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5–MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.
Publisher: American Association for Cancer Research (AACR)
Date: 13-03-2020
DOI: 10.1158/0008-5472.CAN-19-0743
Abstract: Targeting the BMP4–SMAD7 signaling axis presents a novel therapeutic strategy to combat metastatic breast cancer, a disease that has had no reduction in patient mortality over 20 years.
Publisher: Elsevier BV
Date: 10-2021
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2014
Abstract: The authors conclude that morning delivery of chemotherapy was preferred. Meeting patients' expectations will present significant challenges to efficient service provision as caseloads increase.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543851.V1
Abstract: Supplementary Figures S1-S5
Publisher: BMJ
Date: 11-02-2014
Publisher: Wiley
Date: 02-2019
DOI: 10.1002/HSR2.115
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424158
Abstract: Figure S4 demonstrates a role for SMAD7 in mediating the inhibition of metastasis by BMP4.
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.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424152
Abstract: Supplementary methods
Publisher: Proceedings of the National Academy of Sciences
Date: 20-04-2020
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424155
Abstract: Legends for the four supplementary figures.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424158.V1
Abstract: Figure S4 demonstrates a role for SMAD7 in mediating the inhibition of metastasis by BMP4.
Publisher: Wiley
Date: 03-08-2014
Publisher: Frontiers Media SA
Date: 31-01-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424155.V1
Abstract: Legends for the four supplementary figures.
Publisher: Springer Science and Business Media LLC
Date: 03-2022
DOI: 10.1038/S41467-022-28705-X
Abstract: Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.
Publisher: Springer International Publishing
Date: 2019
Publisher: Oxford University Press (OUP)
Date: 17-12-2011
DOI: 10.1093/CID/CIQ050
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543848
Abstract: Supplementary Table S1
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424161.V1
Abstract: Figure S3 shows that BMP4 does not alter migration or invasion in vitro and that BMP7 can also inhibit metastasis.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543851
Abstract: Supplementary Figures S1-S5
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424149
Abstract: PCR primers
Publisher: BMJ
Date: 10-2021
Abstract: Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib–trametinib and ipilimumab–nivolumab have similar intracranial response rates (50%–55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab–nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. Patients who received first-line ipilimumab–nivolumab for MBMs or second/third line ipilimumab–nivolumab for intracranial metastases with BRAF V600 mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded s les of BRAF V600 mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. Twenty-five and 30 patients who received first and second/third line ipilimumab–nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab–nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab–nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab–nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value .05, false discovery rate (FDR) .1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03). Second-line ipilimumab–nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab–nivolumab showed enrichment of the IPRES gene signature.
Publisher: Cold Spring Harbor Laboratory
Date: 13-05-2019
DOI: 10.1101/626952
Abstract: Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by a residual disease that results in relapse. This residual disease is characterized by drug-induced adaptation, that in melanoma includes altered metabolism. Here, we examined how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNAi screen and global gene expression profiling. This systematic approach revealed post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA binding kinase UHMK1 interacts with mRNAs that encode metabolic proteins and selectively controls their transport and translation during adaptation to BRAF targeted therapy. Inactivation of UHMK1 improves metabolic response to BRAF targeted therapy and delays resistance to BRAF and MEK combination therapy in vivo . Our data support a model wherein post-transcriptional gene expression pathways regulate metabolic adaptation underpinning targeted therapy response and suggest inactivation of these pathways may delay disease relapse.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424167.V1
Abstract: Figure S1 shows the association of BMP4 expression with tumour aggressiveness and with metastasis-free survival
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424146
Abstract: BMP4 expression in human breast cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424140.V1
Abstract: BMP4 and SMAD7 in clinical s les
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.JOCN.2022.06.008
Abstract: Medulloblastoma in adult patients is a rare condition with limited contemporary demographic and treatment outcome data available in an Australian population. We conducted a retrospective review of patterns of care and outcomes of adult patients diagnosed with medulloblastoma treated at major neuro-oncology centres across Australia between January 2010 and December 2019. A total of 80 patients were identified and the median follow-up after diagnosis was 59.2 (range 0.5-204) months. A variety of chemotherapy regimens were used in the adjuvant and recurrent settings. The median overall survival (mOS) was 78 months (IQR 17.5-94.8). Patients who had no residual disease post-resection or with SHH-subtype tumours had a numerically longer 5-year survival rate than those with residual disease post resection or non-SHH subtypes respectively. The median time to recurrence from diagnosis was 18.4 months. The median OS from 1st relapse was 22.1 months (95% CI 11.7-31.4) and mOS from second relapse was 10.2 months (95% CI 6.6 - NR). This is the largest dataset examining patterns of care of adult patients with medulloblastoma in an Australian population. Substantial variation existed in the chemotherapy agents used in the adjuvant and recurrent setting. As has been demonstrated in a paediatric population, trials such as the upcoming EORTC 1634-BTG/NOA-23 trial (PersoMed-1 study) which are tailoring treatments to molecular profiles are likely to improve outcome in adult medulloblastoma.
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.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424143
Abstract: Anoikis genes regulated by BMP4
Publisher: Wiley
Date: 26-05-2021
Publisher: Elsevier
Date: 2016
Publisher: Springer Science and Business Media LLC
Date: 21-04-2020
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6511693.V1
Abstract: Abstract Metastasis is the major cause of death in patients with cancer with no therapeutic cure, treatments remain largely palliative. As such, new targets and therapeutic strategies are urgently required. Here, we show that bone morphogenetic protein-4 (BMP4) blocks metastasis in animal models of breast cancer and predicts improved survival in patients. In preclinical models of spontaneous metastasis, BMP4 acted as an autocrine mediator to modulate a range of known metastasis-regulating genes, including i Smad7 /i , via activation of canonical BMP-SMAD signaling. Restored BMP4 expression or therapeutically administered BMP4 protein, blocked metastasis and increased survival by sensitizing cancer cells to anoikis, thereby reducing the number of circulating tumor cells. Gene silencing of i Bmp4 /i or its downstream mediator i Smad7 /i , reversed this phenotype. Administration of recombinant BMP4 markedly reduced spontaneous metastasis to lung and bone. Elevated levels of BMP4 and SMAD7 were prognostic for improved recurrence-free survival and overall survival in patients with breast cancer, indicating the importance of canonical BMP4 signaling in the suppression of metastasis and highlighting new avenues for therapy against metastatic disease. Significance: Targeting the BMP4–SMAD7 signaling axis presents a novel therapeutic strategy to combat metastatic breast cancer, a disease that has had no reduction in patient mortality over 20 years. /
Publisher: Elsevier BV
Date: 09-2020
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424140
Abstract: BMP4 and SMAD7 in clinical s les
Publisher: AME Publishing Company
Date: 08-2020
Publisher: BMJ
Date: 23-11-2016
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. /
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2023
DOI: 10.1200/JCO.2023.41.16_SUPPL.9525
Abstract: 9525 Background: Denosumab (deno) is an antibody directed against Receptor Activator of NF Kappa-b ligand (RANKL) with established indications as a bone anti-resorptive agent in several cancers. Pre-clinical studies and several case series suggest anti-RANKL can enhance the anti-tumor effect of immune checkpoint inhibitors possibly via modulation of Treg and M2 macrophages. We did a multicentre phase Ib/II trial (NCT03161756) to investigate the safety and efficacy of deno in combination with nivolumab (nivo) or ipilimumab-nivolumab (ipi-nivo). Methods: Patients (pts) with unresectable stage III or IV melanoma were recruited to either Arm A (nivo-deno) or Arm B (ipi-nivo-deno) as first-line therapy. In Arm A pts received nivo 3 mg/kg IV q2 weekly for 4 doses and deno 120 mg SC on D1, D8, D15, D29 and then maintenance nivo 480 mg IV with deno 120 mg SC q 4 weekly. In Arm B pts received combined ipi 3mg/kg with nivo 1 mg/kg IV 3 weekly for 4 doses with deno 120 mg SC on D1, D8, D15, D29 followed by 4 weekly maintenance nivo 480 mg with deno 120 mg. Co-primary endpoints were median PFS and grade 3-4 treatment related adverse events (TRAE) of interest. Secondary endpoints were objective response rate (ORR) and overall survival (OS). Results: 27 pts (15 males, median age 67 years, 48% (13/27) stage IVM1c, 26% elevated LDH, 31% BRAF V600 mutant) were enrolled in Arm A and 24 of 25 evaluable pts (16 males, median age 62, 46% (11/24) stage IVM1c, 13% (3/24) stage IVM1d, 30% elevated LDH and 33% BRAF V600 mutant) were enrolled in Arm B. Median follow up was 30.8 months (m) for Arm A and 24.8 m for Arm B. The RECIST 1.1 ORR was 56% (n=15/27, 15% [4/27] complete responses [CR] and 41% [11/27] partial response [PR]) for Arm A and 71% (17/24, 25% [6/24) CR and 46% [11/24] PR) for Arm B. The median PFS in both arms has not been reached with 12 month PFS rates of 59% (95%CI: 43-81) and 63% (95%CI: 46-88) for Arms A & B, respectively. Grade 3-4 TRAE were 11% (3/27) in Arm A and 71% (17/24) in Arm B. Common TRAE (≥10%) in Arm A was rash (52%), pruritus (30%), fatigue (26%), nausea (19%), diarrhoea/colitis (15%), arthralgia (11%), vitiligo (11%), hyperthyroidism (11%). Common TRAE (≥10%) in Arm B included rash (63%), fatigue (54%), diarrhoea/colitis (54%), hepatitis (46%), hyperthyroidism (29%), pneumonitis (29%), pruritus (25%), increased GGT (17%), hypothyroidism (17%), hypocalcaemia (13%). Arm B G3-4 TRAE included diarrhoea/colitis (25%), pneumonitis (17%) and hepatitis (13%). Conclusions: Nivo-deno and ipi-nivo-deno had numerically similar G3-4 TRAE compared to nivo and ipi-nivo. The median PFS, 12 month PFS and ORR for nivo-deno and ipi-nivo-deno are encouraging compared with CHECKMATE 067. Clinical trial information: NCT03161756 . [Table: see text]
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424164.V1
Abstract: Figure S2 shows the effect of BMP4 on the in vitro properties of tumour cells and response of tumours in vivo.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.EJCA.2018.09.027
Abstract: Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed death 1 (anti-PD1)-treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs. The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy. Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated. This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup. Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes.
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. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424143.V1
Abstract: Anoikis genes regulated by BMP4
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2018
DOI: 10.1158/1538-7445.SABCS17-P1-01-09
Abstract: Metastasis is a lethal manifestation of cancer, the development of which is the major cause of death in cancer patients. During a search for metastasis-regulating elements, an inverse correlation was identified between the in vivo tumor expression of bone morphogenetic protein-4 (BMP4) and spontaneous metastasis in a panel of isogenic mammary tumors of varying metastatic capacity. BMP4 is an essential morphogen in development, regulating cellular mechanisms akin to those in metastasis, including cellular differentiation, pluripotency and apoptosis. We therefore initiated an investigation of the impact of BMP4 expression on the metastatic process. We studied the effect of enforced expression of BMP4 in a highly metastatic mammary tumour model called 4T1.2, comparing in vitro properties and tumour progression in mice. There were no differences in proliferation in vitro or when implanted into the mammary gland of immunocompetent mice. In contrast, mice bearing equivalent-sized 4T1.2-BMP4 tumors revealed dramatically reduced metastasis to lung, lymph node and bone. In a parallel study where the established orthotopic primary tumor was resected, survival was significantly extended in mice bearing 4T1.2-BMP4 tumors. Enforced BMP4 expression in tumor cells introduced intravenously resulted in a 2.5-fold decrease in lung metastatic burden, consistent with the impaired capacity of tumor cells to survive in circulation and colonize the lung. Conversely, silencing BMP4 expression in separate weakly metastatic tumours enhanced their ability to colonize the lung and shortened the survival of the mice. No changes were found in the ability of tumor cells expressing BMP4 or treated with recombinant BMP4 to migrate or invade through Matrigel in chemotactic assays but BMP4 enhanced anoikis in both mouse and human breast cancer cells, indicating that BMP4 sensitizes disseminated cells to anoikic stresses induced by cell-substrate detachment and shear flow during systemic transit. BMP4 activated canonical BMP-SMAD signaling in our mammary tumours, leading to altered expression of known metastasis-regulating genes, including SMAD7. SMAD7 depletion in metastasis-deficient 4T1.2-BMP4 tumors accelerated the onset of metastatic disease. In a meta-analysis of 3,587 breast cancer patients in publically available datasets, low BMP4 mRNA expression was significantly associated with reduced relapse-free survival (RFS) (HR = 0.85, P = 0.01). In an independent analysis using the BreastMark algorithm, low levels of BMP4 mRNA were associated with reduced RFS (HR = 0.88, P = 0.035), distant metastasis-free survival (HR = 0.83, P = 0.035) and overall survival (HR = 0.78, P = 0.006). At the protein level, in a tissue microarray from 415 treatment naïve patients, improved overall survival was observed in multivariate analysis for both BMP4 (HR = 0.66, P = 0.037) and SMAD7 expression (HR = 0.64, P = 0.035) in idually. Expression of both proteins compared to neither further improved OS (HR = 0.55, P = 0.005). In summary, we found strong evidence that BMP4 is a metastasis suppressor correlating inversely with metastatic potential in preclinical breast cancer models and predicting improved relapse-free and overall survival in breast cancer patients. Citation Format: Redfern AD, Eckhardt BL, Cao Y, Sloan EK, Parker BS, Loi S, Ueno NT, Lau PK, Latham B, Anderson RL. BMP4 suppresses the progression of breast cancer through altered expression of metastasis regulating genes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium 2017 Dec 5-9 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2018 (4 Suppl):Abstract nr P1-01-09.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.EJCA.2019.09.009
Abstract: Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have transformed the management of many malignancies. Although rare, immune-mediated myocarditis presents unique clinical challenges due to heterogenous presentation, potential life-threatening consequences, and the time-critical need to differentiate it from other causes of cardiac dysfunction. Increasingly, TKI are being combined with ICI to promote immune modulation and improve efficacy. However, these combinations are associated with more toxicities. This series describes six patients with advanced melanoma who developed immune-mediated myocarditis while receiving an anti-PD-1 antibody or an anti-PD-L1 antibody plus a mitogen-activated protein kinase inhibitor. It provides a review of their heterogenous clinical presentations, investigational findings and treatment outcomes. Presentations ranged from asymptomatic cardiac enzyme elevation to death due to heart failure. We highlight the role of cardiac MRI (CMRI), a sensitive and non-invasive tool for the early detection and subsequent monitoring of myocardial inflammation. Five of the six patients exhibited CMRI changes characteristic of myocarditis, including mid-wall myocardial oedema and late gadolinium enhancement in a non-coronary distribution. Critically, two of these patients had normal findings on echocardiogram. Of the five patients who received immunosuppression, four recovered from myocarditis and one died of cardiac failure. The sixth patient improved with cardiac failure management alone. Three of the four patients responding to ICI derived long-term benefit. Clinical vigilance, prompt multimodal diagnosis and multidisciplinary management are paramount for the treatment of immune-mediated myocarditis.
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.
Publisher: Cold Spring Harbor Laboratory
Date: 16-11-2020
DOI: 10.1101/2020.11.11.20226845
Abstract: Distinguishing metastases from new primary malignancies or vice versa is important because misclassification can result in inappropriate management. However, for some cases this distinction can be challenging, particularly for squamous cell carcinomas in which the usual surgical pathology approach, predominantly morphology and immunohistochemistry, are frequently non-contributory. We analysed tumor-associated mutations in order to determine whether they could help with this diagnostic dilemma. Mutations in specific genes were identified with cBioPortal, a large publically available tumor sequence data set. Genes were selected based upon either their high overall prevalence of mutation, or their inclusion in an in-house tumor sequencing set. Tumor types analysed included various common adenocarcinomas, squamous cell carcinomas from multiple sites, urothelial carcinoma and melanoma. In idual mutations and sets of mutations within gene cohorts were compared by their ersity (or heterogeneity) index, prevalence and cumulative prevalence. We demonstrated the utility of this method by performing in-house sequencing of candidate genes in tumors from three patients for which morphology and immunohistochemistry were unable to distinguish between a metastasis and a new primary malignancy. Sequence data from relatively small cohorts of candidate genes readily identified highly erse, low prevalence mutation profiles in most common malignancies including squamous cell carcinomas. The ersity index predicted the likelihood of an identical mutation profile occurring in an unrelated tumor. High yield gene cohorts could be predicted based on the primary tumor type. Most cohorts included TP53 due to both its high mutation prevalence and high mutation index of ersity. Identical, low prevalence mutations in multiple tumors from patients in the three case studies provided strong diagnostic certainty for metastases rather than new primary malignancies. Most common tumors, including squamous cell carcinomas, have a readily identifiable mutation profiles that occur at a sufficiently low prevalence to effectively barcode or fingerprint the tumor. An identical mutation profile in a primary tumor and a new lesion provides strong evidence for a metastasis and effectively excludes a new primary malignancy, providing diagnostic confidence and aiding clinical management certainty.
No related grants have been discovered for Peter Lau.