ORCID Profile
0000-0002-3295-228X
Current Organisations
Sydney Children's Hospital Randwick
,
Royal Australasian College of Physicians
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Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479843.V1
Abstract: Supplementary Figure S4. Combination of the BET bromodomain inhibitor I-BET762 and chemotherapy agents, but not proteasome inhibitors, induces cytotoxicity to normal cells.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Springer Science and Business Media LLC
Date: 15-09-2022
DOI: 10.1186/S12885-022-10072-X
Abstract: Pediatric acute lymphoblastic leukemia (ALL) therapy is accompanied by treatment-related toxicities (TRTs) and impaired quality of life. In Australia and New Zealand, children with ALL are treated with either Children’s Oncology Group (COG) or international Berlin-Frankfurt-Munster (iBFM) Study Group-based therapy. We conducted a prospective registry study to document symptomatic TRTs (venous thrombosis, neurotoxicity, pancreatitis and bone toxicity), compare TRT outcomes to retrospective TRT data, and measure the impact of TRTs on children’s general and cancer-related health-related quality of life (HRQoL) and parents’ emotional well-being. Parents of children with newly diagnosed ALL were invited to participate in the ASSET ( A cute Lymphoblastic Leukaemia S ubtypes and S ide E ffects from T reatment) study and a prospective, longitudinal HRQoL study. TRTs were reported prospectively and families completed questionnaires for general (Healthy Utility Index Mark 3) and cancer specific (Pediatric Quality of Life Inventory (PedsQL)-Cancer Module) health related quality of life as well the Emotion Thermometer to assess emotional well-being. Beginning in 2016, 260 pediatric patients with ALL were enrolled on the TRT registry with a median age at diagnosis of 59 months (range 1–213 months), 144 males (55.4%), majority with Pre-B cell immunophenotype, n = 226 (86.9%), 173 patients (66.5%) treated according to COG platform with relatively equal distribution across risk classification sub-groups. From 2018, 79 families participated in the HRQoL study through the first year of treatment. There were 74 TRT recorded, reflecting a 28.5% risk of developing a TRT. In idual TRT incidence was consistent with previous studies, being 7.7% for symptomatic VTE, 11.9% neurotoxicity, 5.4% bone toxicity and 5.0% pancreatitis. Children’s HRQoL was significantly lower than population norms throughout the first year of treatment. An improvement in general HRQoL, measured by the HUI3, contrasted with the lack of improvement in cancer-related HRQoL measured by the PedsQL Cancer Module over the first 12 months. There were no persisting differences in the HRQoL impact of COG compared to iBFM therapy. It is feasible to prospectively monitor TRT incidence and longitudinal HRQoL impacts during ALL therapy. Early phases of ALL therapy, regardless of treatment platform, result in prolonged reductions in cancer-related HRQoL.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479837.V1
Abstract: Supplementary Figure S6. OTX015 and carfilzomib exert synergistic anticancer effects partly by inducing oxidative stress and endoplasmic reticulum stress.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2009
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479828.V1
Abstract: Supplementary Table S1. Primary screening of the Food and Drug Administration-Approved Oncology Drugs (AODs) Set IV from the US National Cancer Institute for BET bromodomain inhibitor enhancers.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2011
Abstract: Glucocorticoids such as prednisolone and dexamethasone are critical drugs used in multi-agent chemotherapy protocols used to treat acute lymphoblastic leukemia (ALL), and response to glucocorticoids is highly predictive of outcome. The NOD/SCID xenograft mouse model of ALL is a clinically relevant model in which the mice develop a systemic leukemia which retains the fundamental biological characteristics of the original disease. Here we report a study evaluating the NOD/SCID xenograft mouse model to investigate glucocorticoid-induced gene expression. Cells from a glucocorticoid-sensitive xenograft derived from a child with B-cell precursor ALL were inoculated into NOD/SCID mice. When highly engrafted the mice were randomized into groups of 4 to receive dexamethasone 15 mg/kg by intraperitoneal injection or vehicle control. Leukemia cells were harvested from mice spleens at 0, 8, 24 or 48 hours thereafter, and gene expression analyzed on Illumina WG-6_V3 chips, comparing all groups to time 0 hours. The 8 hour dexamethasone-treated timepoint had the highest number of significantly differentially expressed genes, with fewer observed at the 24 and 48 hour timepoints, and with minimal changes seen across the time-matched controls. When compared to publicly available datasets of glucocorticoid-induced gene expression from an in vitro cell line study and from an in vivo study of patients with ALL, at the level of pathways, expression changes in the 8 hour xenograft s les showed a similar response to patients treated with glucocorticoids. Replicate analysis revealed that at the 8 hour timepoint, a dataset with high signal and differential expression, using data from 3 replicates instead of 4 resulted in excellent recovery scores of 0.9. However at other timepoints with less signal very poor recovery scores were obtained with 3 replicates. The NOD/SCID xenograft mouse model provides a reproducible experimental system in which to investigate clinically-relevant mechanisms of drug-induced gene regulation in ALL the 8 hour timepoint provides the highest number of significantly differentially expressed genes time-matched controls are redundant and excellent recovery scores can be obtained with 3 replicates.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479834.V1
Abstract: Supplementary Figure S7. OTX015 and carfilzomib synergistically improve mouse survival in a PDX model of TERT-rearranged neuroblastoma.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/0008-5472.23952251
Abstract: Supplementary Figures
Publisher: Springer Science and Business Media LLC
Date: 12-02-2021
DOI: 10.1038/S41698-021-00145-8
Abstract: The prognosis of recurrent malignant peripheral nerve sheath tumors (MPNST) is dismal, with surgical resection being the only definitive salvage therapy. Treatment with chemoradiation approaches has not significantly improved patient outcomes. Similarly, trials of therapies targeting MPNST genomic drivers have thus far been unsuccessful. Improved understanding of the molecular pathogenesis of MPNST indicates frequent activation of the mitogen-activated protein kinase (MAPK) cell signaling pathway. MEK inhibitors have shown activity in preclinical studies however, their clinical efficacy has not been reported to date. We describe here a case of sustained complete response to MEK inhibition in an adolescent patient with a recurrent metastatic MPNST with multiple alterations in the MAPK pathway, guided by a precision oncology approach.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479846.V1
Abstract: Supplementary Figure S3. Screening for Approved Oncology Drugs (AODs) exerting synergistic anticancer effects with BET bromodomain inhibitors against TERT-rearranged neuroblastoma cells.
Publisher: Informa UK Limited
Date: 17-11-2018
DOI: 10.1080/08880018.2018.1541492
Abstract: Anaplastic lymphoma kinase (ALK) inhibitors such as crizotinib and alectinib have been shown to have significant activity in ALK-rearranged non-small cell lung cancers (NSCLC). There are no data for alectinib's safety or efficacy in younger patients, though it is superior to crizotinib in adult trials. We present a 14-year old girl diagnosed with stage IV-B ALK-positive adenocarcinoma of the lung after presenting with cough and fever. She was commenced on alectinib at adult dose and has had sustained complete metabolic remission for 9 months. She is the youngest patient with lung adenocarcinoma to be treated with alectinib.
Publisher: Wiley
Date: 11-2005
Publisher: Elsevier BV
Date: 10-2021
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479831.V1
Abstract: Re - Revised Supplementary Materials & Methods
Publisher: Wiley
Date: 03-06-2013
DOI: 10.1002/PBC.24559
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479852.V1
Abstract: Supplementary Figure S1. TERT induces TERT-rearranged neuroblastoma cell proliferation and cell cycle progression through a telomerase-independent mechanism.
Publisher: Springer Science and Business Media LLC
Date: 09-2022
DOI: 10.1038/S41416-021-01538-Z
Abstract: Minimal residual disease (MRD) measurement is a cornerstone of contemporary acute lymphoblastic leukaemia (ALL) treatment. The presence of immunoglobulin (Ig) and T cell receptor (TCR) gene recombinations in leukaemic clones allows widespread use of patient-specific, DNA-based MRD assays. In contrast, paediatric solid tumour MRD remains experimental and has focussed on generic assays targeting tumour-specific messenger RNA, methylated DNA or microRNA. We examined the feasibility of using whole-genome sequencing (WGS) data to design tumour-specific polymerase chain reaction (PCR)-based MRD tests (WGS-MRD) in 18 children with high-risk relapsed cancer, including ALL, high-risk neuroblastoma (HR-NB) and Ewing sarcoma (EWS) ( n = 6 each). Sensitive WGS-MRD assays were generated for each patient and allowed quantitation of 1 tumour cell per 10 −4 (0.01%)–10 –5 (0.001%) mononuclear cells. In ALL, WGS-MRD and Ig/TCR-MRD were highly concordant. WGS-MRD assays also showed good concordance between quantitative PCR and droplet digital PCR formats. In serial clinical s les, WGS-MRD correlated with disease course. In solid tumours, WGS-MRD assays were more sensitive than RNA-MRD assays. WGS facilitated the development of patient-specific MRD tests in ALL, HR-NB and EWS with potential clinical utility in monitoring treatment response. WGS data could be used to design patient-specific MRD assays in a broad range of tumours.
Publisher: Elsevier BV
Date: 12-2018
Publisher: Cambridge University Press (CUP)
Date: 17-08-2015
DOI: 10.1017/ICE.2015.179
Abstract: Computerized decision support systems (CDSSs) can provide indication-specific antimicrobial recommendations and approvals as part of hospital antimicrobial stewardship (AMS) programs. The aim of this study was to assess the performance of a CDSS for surveillance of invasive fungal infections (IFIs) in an inpatient hematology/oncology cohort. Between November 1, 2012, and October 31, 2013, pediatric hematology/oncology inpatients diagnosed with an IFI were identified through an audit of the CDSS and confirmed by medical record review. The results were compared to hospital diagnostic-related group (DRG) coding for IFI throughout the same period. A total of 83 patients were prescribed systemic antifungals according to the CDSS for the 12-month period. The CDSS correctly identified 19 patients with IFI on medical record review, compared with 10 patients identified by DRG coding, of whom 9 were confirmed to have IFI on medical record review. CDSS was superior to diagnostic coding in detecting IFI in an inpatient pediatric hematology/oncology cohort. The functionality of CDSS lends itself to inpatient infectious diseases surveillance but depends on prescriber adherence. Infect. Control Hosp. Epidemiol. 2015 (11):1313–1317
Publisher: Frontiers Media SA
Date: 12-05-2022
DOI: 10.3389/FMOLB.2022.885597
Abstract: The measurement of circulating tumor DNA (ctDNA) has gained increasing prominence as a minimally invasive tool for the detection of cancer-specific markers in plasma. In adult cancers, ctDNA detection has shown value for disease-monitoring applications including tumor mutation profiling, risk stratification, relapse prediction, and treatment response evaluation. To date, there are ctDNA tests used as companion diagnostics for adult cancers and it is not understood why the same cannot be said about childhood cancer, despite the marked differences between adult and pediatric oncology. In this review, we discuss the current understanding of ctDNA as a disease monitoring biomarker in the context of pediatric malignancies, including the challenges associated with ctDNA detection in liquid biopsies. The data and conclusions from pediatric cancer studies of ctDNA are summarized, highlighting treatment response, disease monitoring and the detection of subclonal disease as applications of ctDNA. While the data from retrospective studies highlight the potential of ctDNA, large clinical trials are required for ctDNA analysis for routine clinical use in pediatric cancers. We outline the requirements for the standardization of ctDNA detection in pediatric cancers, including s le handling and reproducibility of results. With better understanding of the advantages and limitations of ctDNA and improved detection methods, ctDNA analysis may become the standard of care for patient monitoring in childhood cancers.
Publisher: Wiley
Date: 13-12-2011
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2023
DOI: 10.1200/PO.18.00297
Abstract: Before anaplastic lymphoma kinase (ALK) inhibitors, treatment options for ALK-positive inflammatory myofibroblastic tumors (AP-IMTs) were unsatisfactory. We retrospectively analyzed the outcome of patients with AP-IMT treated with crizotinib to document response, toxicity, survival, and features associated with relapse. The cohort comprised eight patients with AP-IMT treated with crizotinib and surgery. Outcome measures were progression-free and overall survival after commencing crizotinib, treatment-related toxicities, features associated with relapse, outcome after relapse, and outcome after ceasing crizotinib. The median follow-up after commencing crizotinib was 3 years (range, 0.9 to 5.5 years). The major toxicity was neutropenia. All patients responded to crizotinib. Five were able to discontinue therapy without recurrence (median treatment duration, 1 year range, 0.2 to 3.0 years) one continues on crizotinib. Two critically ill patients with initial complete response experienced relapse while on therapy. Both harbored RANBP2-ALK fusions and responded to alternative ALK inhibitors one ultimately died as a result of progressive disease, whereas the other remains alive on treatment. Progression-free and overall survival since commencement of crizotinib is 0.75 ± 0.15% and 0.83 ± 0.15%, respectively. We confirm acceptable toxicity and excellent disease control in patients with AP-IMT treated with crizotinib, which may be ceased without recurrence in most. Relapses occurred in two of three patients with RANBP2-ALK translocated IMT, which suggests that such patients require additional therapy.
Publisher: Elsevier BV
Date: 08-2021
DOI: 10.1016/J.CURRPROBLCANCER.2021.100768
Abstract: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor of intermediate malignant potential that predominantly affects children, adolescents and young adults. IMT has a predilection for the lung, abdomen, pelvis, and retroperitoneum, however, can affect any part of the body. IMT is typically localized, and multifocal or metastatic disease is uncommon. Complete surgical resection is the treatment of choice when feasible. There is no established standard of care for unresectable and advanced IMT. Approximately half of IMTs harbor anaplastic lymphoma kinase (ALK) gene rearrangements, and fusions involving ROS1, PDGFRβ, RET and NTRK have also been described. Given the molecular landscape of IMT, management of these tumors has evolved to include tyrosine kinase inhibitors and novel targeted therapeutics. This review highlights the molecular characteristics, evolution of targeted therapies and the remaining challenges in the management of IMT.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.CANLET.2016.02.021
Abstract: Tripartite Motif-containing protein 16 (TRIM16) is a member of a large family of tripartite motif (TRIM) proteins, that has been implicated in the pathogenesis of multiple cancers. However, the mechanism by which TRIM16 acts as a tumour suppressor is currently unknown. We used the versatile yeast two-hybrid assay on a cDNA library from human testes, which has relative high TRIM16 expression, to identify potential TRIM16-binding proteins. We identified transactive response DNA-binding protein 43 (TDP43) as a novel TRIM16 binding protein. Co-immunoprecipitation assay demonstrated that TDP43 bound TRIM16 in neuroblastoma and breast cancer cells. Enforced over-expression of TRIM16 increased the protein half-life of TDP43, through the inhibition of the proteosomal degradation pathway. High levels of TRIM16 and TDP43 are associated with good prognosis in both human neuroblastoma and breast cancer tissues. Importantly, we found TDP43 expression was required for TRIM16-induced inhibition of neuroblastoma and breast cancer cell growth and the repressive effect of TRIM16 on cell cycle regulatory proteins, E2F1 and pRb. Taken together, our data suggest that TRIM16 and TDP43 are both good prognosis indicators also we showed that TRIM16 inhibits cancer cell viability by a novel mechanism involving interaction and stabilisation of TDP43 with consequent effects on E2F1 and pRb proteins.
Publisher: SAGE Publications
Date: 09-02-2018
Abstract: Although MYCN (aka N-myc) lification is reported in ∼20% of neuroblastomas, MYC (aka C-myc) lification appears to be a rare event in this disease. As of today, only 2 MYC- lified neuroblastomas have been briefly mentioned in the literature. We studied here the clinicopathological features of 3 MYC- lified neuroblastomas. All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively. Further analysis on 2 tumors revealed unfavorable histology with MYC protein overexpression but with neither MYCN lification nor MYCN protein overexpression. Both of these tumors exhibited “large cell neuroblastoma” histology with enlarged, uniquely open nuclei and nucleolar hypertrophy, along with “aberrant” desmin expression. MYC- lified neuroblastomas are extremely rare and seem to present with distinct clinicopathological features.
Publisher: Wiley
Date: 06-2021
Abstract: Copper is an essential transition metal frequently increased in cancer known to strongly influence essential cellular processes. Targeted therapy protocols utilizing both novel and repurposed drug agents initially demonstrate strong efficacy, before failing in advanced cancers as drug resistance develops and relapse occurs. Overcoming this limitation involves the development of strategies and protocols aimed at a wider targeting of the underlying molecular changes. Receptor Tyrosine Kinase signaling pathways, epigenetic mechanisms and cell metabolism are among the most common therapeutic targets, with molecular investigations increasingly demonstrating the strong influence each mechanism exerts on the others. Interestingly, all these mechanisms can be influenced by intracellular copper. We propose that copper chelating agents, already in clinical trial for multiple cancers, may simultaneously target these mechanisms across a wide variety of cancers, serving as an excellent candidate for targeted combination therapy. This review summarizes the known links between these mechanisms, copper, and copper chelation therapy.
Publisher: Elsevier BV
Date: 08-2020
DOI: 10.1016/J.CCELL.2020.05.014
Abstract: Signals driving aberrant self-renewal in the heterogeneous leukemia stem cell (LSC) pool determine aggressiveness of acute myeloid leukemia (AML). We report that a positive modulator of canonical WNT signaling pathway, RSPO-LGR4, upregulates key self-renewal genes and is essential for LSC self-renewal in a subset of AML. RSPO2/3 serve as stem cell growth factors to block differentiation and promote proliferation of primary AML patient blasts. RSPO receptor, LGR4, is epigenetically upregulated and works through cooperation with HOXA9, a poor prognostic predictor. Blocking the RSPO3-LGR4 interaction by clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewal and induces differentiation in AML patient-derived xenografts but does not affect normal hematopoietic stem cells, providing a therapeutic opportunity for HOXA9-dependent leukemia.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479837
Abstract: Supplementary Figure S6. OTX015 and carfilzomib exert synergistic anticancer effects partly by inducing oxidative stress and endoplasmic reticulum stress.
Publisher: Elsevier BV
Date: 2021
DOI: 10.2139/SSRN.3844779
Publisher: EMBO
Date: 20-12-2022
Publisher: Wiley
Date: 08-08-2019
DOI: 10.1002/PPUL.24456
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000210
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 30-11-2015
DOI: 10.1158/0008-5472.CAN-15-0423
Abstract: MYCN gene lification in neuroblastoma drives a gene expression program that correlates strongly with aggressive disease. Mechanistically, trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a strict prerequisite for this transcriptional program to be enacted. WDR5 is a histone H3K4 presenter that has been found to have an essential role in H3K4 trimethylation. For this reason, in this study, we investigated the relationship between WDR5-mediated H3K4 trimethylation and N-Myc transcriptional programs in neuroblastoma cells. N-Myc upregulated WDR5 expression in neuroblastoma cells. Gene expression analysis revealed that WDR5 target genes included those with MYC-binding elements at promoters such as MDM2. We showed that WDR5 could form a protein complex at the MDM2 promoter with N-Myc, but not p53, leading to histone H3K4 trimethylation and activation of MDM2 transcription. RNAi-mediated attenuation of WDR5 upregulated expression of wild-type but not mutant p53, an effect associated with growth inhibition and apoptosis. Similarly, a small-molecule antagonist of WDR5 reduced N-Myc/WDR5 complex formation, N-Myc target gene expression, and cell growth in neuroblastoma cells. In MYCN-transgenic mice, WDR5 was overexpressed in precancerous ganglion and neuroblastoma cells compared with normal ganglion cells. Clinically, elevated levels of WDR5 in neuroblastoma specimens were an independent predictor of poor overall survival. Overall, our results identify WDR5 as a key cofactor for N-Myc–regulated transcriptional activation and tumorigenesis and as a novel therapeutic target for MYCN- lified neuroblastomas. Cancer Res 75(23) 5143–54. ©2015 AACR.
Publisher: Wiley
Date: 26-02-2021
Publisher: Wiley
Date: 17-12-2014
DOI: 10.1111/GCB.12758
Abstract: Predicting rice ( Oryza sativa ) productivity under future climates is important for global food security. Ecophysiological crop models in combination with climate model outputs are commonly used in yield prediction, but uncertainties associated with crop models remain largely unquantified. We evaluated 13 rice models against multi‐year experimental yield data at four sites with erse climatic conditions in Asia and examined whether different modeling approaches on major physiological processes attribute to the uncertainties of prediction to field measured yields and to the uncertainties of sensitivity to changes in temperature and CO 2 concentration [ CO 2 ]. We also examined whether a use of an ensemble of crop models can reduce the uncertainties. In idual models did not consistently reproduce both experimental and regional yields well, and uncertainty was larger at the warmest and coolest sites. The variation in yield projections was larger among crop models than variation resulting from 16 global climate model‐based scenarios. However, the mean of predictions of all crop models reproduced experimental data, with an uncertainty of less than 10% of measured yields. Using an ensemble of eight models calibrated only for phenology or five models calibrated in detail resulted in the uncertainty equivalent to that of the measured yield in well‐controlled agronomic field experiments. Sensitivity analysis indicates the necessity to improve the accuracy in predicting both biomass and harvest index in response to increasing [ CO 2 ] and temperature.
Publisher: Springer Science and Business Media LLC
Date: 27-01-2020
DOI: 10.1007/S10555-020-09855-0
Abstract: Informative and realistic mouse models of high-risk neuroblastoma are central to understanding mechanisms of tumour initiation, progression, and metastasis. They also play vital roles in validating tumour drivers and drug targets, as platforms for assessment of new therapies and in the generation of drug sensitivity data that can inform treatment decisions for in idual patients. This review will describe genetically engineered mouse models of specific subsets of high-risk neuroblastoma, the development of patient-derived xenograft models that more broadly represent the ersity and heterogeneity of the disease, and models of primary and metastatic disease. We discuss the research applications, advantages, and limitations of each model type, the importance of model repositories and data standards for supporting reproducible, high-quality research, and potential future directions for neuroblastoma mouse models.
Publisher: Elsevier BV
Date: 04-2017
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000213
Abstract: Supplementary Figures 1-7 and Figure Legends
Publisher: American Association for the Advancement of Science (AAAS)
Date: 30-01-2019
DOI: 10.1126/SCITRANSLMED.AAU1099
Abstract: MYCN regulates polyamines in neuroblastoma, and combined inhibition of polyamine synthesis and transport has therapeutic effects in mouse models.
Publisher: Mary Ann Liebert Inc
Date: 2001
Abstract: Peripheral nervous system (PNS) sensory neurons are directly involved in the pathophysiology of numerous inherited and acquired neurological conditions. Therefore, efficient and stable gene delivery to these postmitotic cells has significant therapeutic potential. Among contemporary vector systems capable of neuronal transduction, only those based on herpes simplex virus have been extensively evaluated in PNS neurons. We therefore investigated the transduction performance of recombinant adeno-associated virus type 2 (AAV) and VSV-G-pseudotyped lentivirus vectors derived from human immunodeficiency virus (HIV-1) in newborn mouse and fetal human dorsal root ganglia (DRG) sensory neurons. In dissociated mouse DRG cultures both vectors achieved efficient transduction of sensory neurons at low multiplicities of infection (MOIs) and sustained transgene expression within a 28-day culture period. Interestingly, the lentivirus vector selectively transduced neurons in murine cultures, in contrast to human cultures, in which Schwann and fibroblast-like cells were also transduced. Recombinant AAV transduced all three cell types in both mouse and human cultures. After direct microinjection of murine DRG explants, maximal transduction efficiencies of 20 and 200 transducing units per neuronal transductant were achieved with AAV and lentivirus vectors, respectively. Most importantly, both vectors achieved efficient and sustained transduction of human sensory neurons in dissociated cultures, thereby directly demonstrating the exciting potential of these vectors for gene therapy applications in the PNS.
Publisher: Mary Ann Liebert Inc
Date: 04-2019
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479840
Abstract: Supplementary Figure S5. BET bromodomain inhibitors and proteasome inhibitors exert synergistic anticancer effects against TERT-rearranged neuroblastoma cells.
Publisher: Springer Science and Business Media LLC
Date: 11-12-2012
DOI: 10.1038/LEU.2012.361
Abstract: Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 β-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL s les, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479846
Abstract: Supplementary Figure S3. Screening for Approved Oncology Drugs (AODs) exerting synergistic anticancer effects with BET bromodomain inhibitors against TERT-rearranged neuroblastoma cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479843
Abstract: Supplementary Figure S4. Combination of the BET bromodomain inhibitor I-BET762 and chemotherapy agents, but not proteasome inhibitors, induces cytotoxicity to normal cells.
Publisher: Springer Science and Business Media LLC
Date: 22-04-2008
DOI: 10.1038/NCPONC1112
Abstract: A 9-month-old boy with Proteus syndrome and a de novo germline mutation in the tumor suppressor PTEN was referred to a specialist centre for management. Over the first years of life, the patient developed life-threatening respiratory dysfunction and malnutrition because of progressive growth of hamartomas affecting the chest, mediastinum, abdomen and pelvis. Physical examination, CT scans of the mediastinum, pelvis and abdomen, measurement of serum insulin-like growth factor binding protein-2, and investigation of the effect of the PTEN mutation on phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling in an in vitro cell model. PTEN hamartoma tumor syndrome, specifically Proteus syndrome. Oral rapamycin.
Publisher: Wiley
Date: 03-11-2012
DOI: 10.1111/J.1440-1754.2011.02212.X
Abstract: Glucocorticoids (GCs), such as prednisolone and dexamethasone, are key components in multi-agent chemotherapy protocols used for the treatment of acute lymphoblastic leukaemia (ALL). Approximately 10% of children with ALL will respond poorly to GCs, and GC resistance is associated with a significantly inferior outcome. This review summarises the current knowledge of GC resistance in ALL, including the roles of the GC receptor and its co-chaperone molecules, the pro-apoptotic and pro-survival B-cell lymphoma 2 family members and alternative non-apoptotic mechanisms of cell death. It concludes with a discussion on therapeutic attempts to overcome GC resistance.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.C.6767498
Abstract: Abstract For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed i in vitro /i screening of 125 patient-derived s les against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in i NTRK /i , i BRAF /i , and i ALK /i and responses to matching targeted drugs. The i in vitro /i results were further validated in patient-derived xenograft models i in vivo /i and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers. Significance: Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers. /
Publisher: Wiley
Date: 03-06-2021
DOI: 10.1002/PON.5740
Abstract: Survivors of adolescent and young adult (AYA) cancer report deficits in social functioning relative to healthy peers. Identifying factors related to their social functioning is critical to improve their long‐term social outcomes. This review addressed: (1) How is social functioning defined and measured among studies of AYAs who have had cancer? (2) What factors have quantitatively/qualitatively are associated with redictors of social functioning? and (3) What associated factors redictors of social functioning are modifiable and amenable to intervention? A systematic review was conducted to identify publications from 2000 to 2021, meeting these criteria: (1) mean/median age at diagnosis/treatment 13–40, (2) assessed social functioning with a validated measure and included factors associated with redictive of social functioning and/or qualitatively assessed young people's perceptions of factors related to their social functioning and (3) was peer‐reviewed ublished in English. Thirty‐seven publications were included. Definitions and measures of social functioning varied, and factors related to social functioning varied based on definition. Factors most commonly associated with decreased social functioning included treatment status (receiving or completed treatment), poor physical functioning, depression, negative body image, engaging in social comparisons, social/cultural stigma around cancer, and fatigue. Increased social functioning was most commonly associated with social support and the quality/age‐appropriateness of care. Social functioning is multidimensional construct for AYAs diagnosed with cancer and may not be adequately assessed with measures of adjustment or quality of life. Future studies should clarify how to optimally define and measure social functioning in this population, to ensure their functioning can be protected and promoted long‐term.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479828
Abstract: Supplementary Table S1. Primary screening of the Food and Drug Administration-Approved Oncology Drugs (AODs) Set IV from the US National Cancer Institute for BET bromodomain inhibitor enhancers.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-03-2023
Abstract: Gene expression noise is known to promote stochastic drug resistance through the elevated expression of in idual genes in rare cancer cells. However, we now demonstrate that chemoresistant neuroblastoma cells emerge at a much higher frequency when the influence of noise is integrated across multiple components of an apoptotic signaling network. Using a JNK activity biosensor with longitudinal high-content and in vivo intravital imaging, we identify a population of stochastic, JNK-impaired, chemoresistant cells that exist because of noise within this signaling network. Furthermore, we reveal that the memory of this initially random state is retained following chemotherapy treatment across a series of in vitro, in vivo, and patient models. Using matched PDX models established at diagnosis and relapse from in idual patients, we show that HDAC inhibitor priming cannot erase the memory of this resistant state within relapsed neuroblastomas but improves response in the first-line setting by restoring drug-induced JNK activity within the chemoresistant population of treatment-naïve tumors.
Publisher: Elsevier BV
Date: 09-2017
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530307.V1
Abstract: AbstractPurpose: i TERT /i gene rearrangement with transcriptional superenhancers leads to i TERT /i overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with i TERT /i -rearranged neuroblastoma. Experimental Design: Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with i TERT /i -rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. Results: The BET bromodomain protein BRD4 promoted i TERT /i -rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced i TERT /i -rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with i TERT /i -rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. Conclusions: OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with i TERT /i -rearranged neuroblastoma. /
Publisher: Springer Science and Business Media LLC
Date: 22-08-2013
DOI: 10.1038/BJC.2013.498
Publisher: Frontiers Media SA
Date: 10-02-2022
Abstract: Despite intensive chemotherapy regimens, up to 60% of adults with acute myeloid leukaemia (AML) will relapse and eventually succumb to their disease. Recent studies suggest that leukaemic stem cells (LSCs) drive AML relapse by residing in the bone marrow niche and adapting their metabolic profile. Metabolic adaptation and LSC plasticity are novel hallmarks of leukemogenesis that provide important biological processes required for tumour initiation, progression and therapeutic responses. These findings highlight the importance of targeting metabolic pathways in leukaemia biology which might serve as the Achilles’ heel for the treatment of AML relapse. In this review, we highlight the metabolic differences between normal haematopoietic cells, bulk AML cells and LSCs. Specifically, we focus on four major metabolic pathways dysregulated in AML (i) glycolysis (ii) mitochondrial metabolism (iii) amino acid metabolism and (iv) lipid metabolism. We then outline established and emerging drug interventions that exploit metabolic dependencies of leukaemic cells in the treatment of AML. The metabolic signature of AML cells alters during different biological conditions such as chemotherapy and quiescence. Therefore, targeting the metabolic vulnerabilities of these cells might selectively eradicate them and improve the overall survival of patients with AML.
Publisher: Elsevier BV
Date: 2017
Publisher: MDPI AG
Date: 23-06-2023
DOI: 10.3390/JPM13071033
Abstract: Precision medicine programs aim to utilize novel technologies to identify personalized treatments for children with cancer. Delivering these programs requires interdisciplinary efforts, yet the many groups involved are understudied. This study explored the experiences of a broad range of professionals delivering Australia’s first precision medicine trial for children with poor-prognosis cancer: the PRecISion Medicine for Children with Cancer (PRISM) national clinical trial of the Zero Childhood Cancer Program. We conducted semi-structured interviews with 85 PRISM professionals from eight professional groups, including oncologists, surgeons, clinical research associates, scientists, genetic professionals, pathologists, animal care technicians, and nurses. We analyzed interviews thematically. Professionals shared that precision medicine can add complexity to their role and result in less certain outcomes for families. Although many participants described experiencing a greater emotional impact from their work, most expressed very positive views about the impact of precision medicine on their profession and its future potential. Most reported navigating precision medicine without formal training. Each group described unique challenges involved in adapting to precision medicine in their profession. Addressing training gaps and meeting the specific needs of many professional groups involved in precision medicine will be essential to ensure the successful implementation of standard care.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479831
Abstract: Re - Revised Supplementary Materials & Methods
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479840.V1
Abstract: Supplementary Figure S5. BET bromodomain inhibitors and proteasome inhibitors exert synergistic anticancer effects against TERT-rearranged neuroblastoma cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479834
Abstract: Supplementary Figure S7. OTX015 and carfilzomib synergistically improve mouse survival in a PDX model of TERT-rearranged neuroblastoma.
Publisher: Mary Ann Liebert Inc
Date: 04-2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-08-2021
DOI: 10.1200/JCO.20.03144
Abstract: Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]). Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged 1 year with MYCN lification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS. A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with MYCN lification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 ( P = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 ( P = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 ( P = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) ( P .001) infection 35% versus 25% ( P = .011) stomatitis 25% versus 3% ( P .001) nausea and vomiting 17% versus 7% ( P .001) and diarrhea 7% versus 3% ( P = .011). No difference in outcome was observed between rCOJEC and MSKCC-N5 however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.EJCA.2021.08.022
Abstract: The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and lification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers (ii) Provide an overview of the development of ALK inhibitors for children (iii) Identify the unmet needs taking into account planned or current ongoing trials (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2023
DOI: 10.1158/0008-5472.23808560.V1
Abstract: Supplementary Figures
Publisher: Springer Science and Business Media LLC
Date: 20-08-2012
DOI: 10.1038/ONC.2012.368
Abstract: Embryonal cancer can arise from postnatally persistent embryonal remnant or rest cells, which are uniquely characterized by the absence of p53 mutations. Perinatal overexpression of the MycN oncoprotein in embryonal cancer precursor cells causes postnatal rests, and later tumor formation through unknown mechanisms. However, overexpression of Myc in adult tissues normally activates apoptosis and/or senescence signals as an organismal defense mechanism against cancer. Here, we show that perinatal neuroblastoma precursor cells exhibited a transiently diminished p53 response to MycN oncoprotein stress and resistance to trophic factor withdrawal, compared with their adult counterpart cells from the TH-MYCN(+/+) transgenic mouse model of neuroblastoma. The adult stem cell maintenance factor and Polycomb group protein, Bmi1 (B-cell-specific Moloney murine leukemia virus integration site), had a critical role at neuroblastoma initiation in the model, by repressing p53 responses in precursor cells. We further show in neuroblastoma tumor cells that Bmi1 could directly bind p53 in a complex with other Polycomb complex proteins, Ring1A or Ring1B, leading to increased p53 ubiquitination and degradation. Repressed p53 signal responses were also seen in precursor cells for other embryonal cancer types, medulloblastoma and acute lymphoblastic leukemia. Collectively, these date indicate a general mechanism for p53 inactivation in some embryonal cell types and consequent susceptibility to MycN oncogenesis at the point of embryonal tumor initiation.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.THROMRES.2019.04.011
Abstract: Symptomatic venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity, which occurs early in childhood acute lymphoblastic leukemia (ALL) therapy. Approximately 5% of children will experience VTE which is treated with anticoagulation. Asparaginase and corticosteroids are etiologic factors for VTE, however other clinical factors may modify this risk. We sought to i) assess published pre-treatment VTE risk factors ii) identify early clinical factors that were associated with VTE and iii) determine whether single nucleotide polymorphisms (SNPs) associated with VTE in non-cancer patients contributed to VTE in children with ALL. We performed a detailed, retrospective analysis of 1021 ALL patients treated between 1998 and 2013. In idual patient records were reviewed to ascertain VTE incidence and document treatment-related clinical variables. The incidence of VTE was 5.1%. Extremes of weight at diagnosis ( 95th centile) was an independent risk factor in multivariable analysis, when added to published risk factors of age ≥10 years and mediastinal mass. When factors during induction/consolidation were considered separately: bacteremia, elevated serum gamma-glutamyl transferase and bilirubin were associated with VTE occurrence. None of the SNPs associated with VTE in non-cancer populations were significantly associated with VTE in our cohort. We found two known risk factors (age ≥ 10 years and mediastinal mass) in a large cohort of children treated for ALL and identified other factors associated with VTE such as weight extremes at diagnosis, bacteremia, and abnormal liver function which warrant further study. These VTE risk factors may form the basis of future thromboprophylaxis trials.
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2023
DOI: 10.1158/0008-5472.23808560
Abstract: Supplementary Figures
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.JPROT.2013.10.032
Abstract: The majority of patients diagnosed with neuroblastoma present with aggressive disease. Improved detection of neuroblastoma cancer cells following initial therapy may help in stratifying patient outcome and monitoring for relapse. To identify potential plasma biomarkers, we utilised a liquid chromatography-tandem mass spectrometry-based proteomics approach to detect differentially-expressed proteins in serum from TH-MYCN mice. TH-MYCN mice carry multiple copies of the human MYCN oncogene in the germline and homozygous mice for the transgene develop neuroblastoma in a manner resembling the human disease. The abundance of plasma proteins was measured over the course of disease initiation and progression. A list of 86 candidate plasma biomarkers was generated. Pathway analysis identified significant association of these proteins with genes involved in the complement system. One candidate, complement C3 protein, was significantly enriched in the plasma of TH-MYCN(+/+) mice at both 4 and 6weeks of age, and was found to be elevated in a cohort of human neuroblastoma plasma s les, compared to healthy subjects. In conclusion, we have demonstrated the suitability of the TH-MYCN(+/+) mouse model of neuroblastoma for identification of novel disease biomarkers in humans, and have identified Complement C3 as a candidate plasma biomarker for measuring disease state in neuroblastoma patients. This study has utilised a unique murine model which develops neuroblastoma tumours that are biologically indistinguishable from human neuroblastoma. This animal model has effectively allowed the identification of plasma proteins which may serve as potential biomarkers of neuroblastoma. Furthermore, the label-free ion count quantitation technique which was used displays significant benefits as it is less labour intensive, feasible and accurate. We have been able to successfully validate this approach by confirming the differential abundance of two different plasma proteins. In addition, we have been able to confirm that the candidate biomarker Complement C3, is more abundant in the plasma of human neuroblastoma patient plasma s les when compared to healthy counterparts. Overall we have demonstrated that this approach can be potentially useful in the identification of biomarker candidates, and that further validation of the candidates may lead to the discovery of novel, clinically useful diagnostic tools in the detection of sub-clinical neuroblastoma.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 11-02-2022
DOI: 10.3324/HAEMATOL.2020.268565
Abstract: Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28–4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.
Publisher: Wiley
Date: 06-03-2017
DOI: 10.1002/PBC.26489
Abstract: Children with acute lymphoblastic leukemia (ALL) undergo intense anticancer treatment. We systematically reviewed 22 studies evaluating 2,073 ALL patients' health-related quality of life (HRQL) and its clinical/demographic correlates during treatment. Overall HRQL was significantly reduced on treatment. Despite HRQL improvements over time, longitudinal studies reported a proportion of children continued to experience reduced HRQL after treatment completion. We found inconsistent associations between clinical/demographic factors and HRQL outcomes. Tentative evidence emerged for worse HRQL being associated with intensive phases of chemotherapy, corticosteroid therapy, experiencing greater toxicity, older age, and female sex. Longitudinal studies are needed to identify children at-risk of reduced HRQL.
Publisher: Mary Ann Liebert Inc
Date: 04-2022
Publisher: Springer Science and Business Media LLC
Date: 10-01-2020
DOI: 10.1038/S41416-019-0682-4
Abstract: Predictive preclinical models play an important role in the assessment of new treatment strategies and as avatar models for personalised medicine however, reliable and timely model generation is challenging. We investigated the feasibility of establishing patient-derived xenograft (PDX) models of high-risk neuroblastoma from a range of tumour-bearing patient materials and assessed approaches to improve engraftment efficiency. PDX model development was attempted in NSG mice by using tumour materials from 12 patients, including primary and metastatic solid tumour s les, bone marrow, pleural fluid and residual cells from cytogenetic analysis. Subcutaneous, intramuscular and orthotopic engraftment were directly compared for three patients. PDX models were established for 44% (4/9) of patients at diagnosis and 100% (5/5) at relapse. In one case, attempted engraftment from pleural fluid resulted in an EBV-associated atypical lymphoid proliferation. Xenogeneic graft versus host disease was observed with attempted engraftment from lymph node and bone marrow tumour s les but could be prevented by T-cell depletion. Orthotopic engraftment was more efficient than subcutaneous or intramuscular engraftment. High-risk neuroblastoma PDX models can be reliably established from erse s le types. Orthotopic implantation allows more rapid model development, increasing the likelihood of developing an avatar model within a clinically useful timeframe.
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2023
DOI: 10.1158/0008-5472.CAN-22-3702
Abstract: Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479849
Abstract: Supplementary Figure S2. BRD4 is required for TERT expression and cell proliferation in TERT-rearranged neuroblastoma cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2023
DOI: 10.1158/0008-5472.C.6767498.V1
Abstract: Abstract For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed i in vitro /i screening of 125 patient-derived s les against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in i NTRK /i , i BRAF /i , and i ALK /i and responses to matching targeted drugs. The i in vitro /i results were further validated in patient-derived xenograft models i in vivo /i and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers. Significance: Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers. /
Publisher: Wiley
Date: 05-10-2018
DOI: 10.1111/JPC.14248
Abstract: Approximately 20-30% of children/adolescents with cancer will not respond to standard therapies. These children are usually offered experimental treatment in the form of an early-phase clinical trial. We examined the perspectives of health-care professionals (HCPs) regarding obtaining informed consent for early-phase trials in paediatric oncology. We collected survey data from 87 HCPs working in paediatric cancer centres across Australia and New Zealand. HCPs were, on average, 44 years old (range = 25-74), with 15.8 years' experience in paediatric oncology (range = 1-40). Few HCPs (17.4%) received training for early-phase trial consent however, most were willing to attend training (77.9%). HCPs (61.6%) reported that they informed families about early-phase trials without any attempt to influence their decision. However, 23.3% of HCPs reported that they informed families that their child would benefit. HCPs' main obstacle in obtaining consent was their perception of parents' eagerness to 'try anything' (52.3%). HCPs perceived that many parents misunderstood key clinical trials concepts, with 25.2% of HCPs believing that not being given clear information influenced parents' decisions. Physicians were more likely than social workers/nurses to inform families that other children will benefit from enrolment in the study. Social workers/nurses appeared to rate the chance of benefits for the patient higher than physicians. HCPs may experience difficulty conducting early-phase trial consultations and obtaining valid informed consent. Our study highlights the need for formal training for HCPs and additional patient education tools.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2020
Publisher: American Association for Cancer Research (AACR)
Date: 02-2017
DOI: 10.1158/1541-7786.MCR-17-0569
Abstract: Mixed lineage leukemia (MLL) gene rearrangements characterize approximately 70% of infant and 10% of adult and therapy-related leukemia. Conventional clinical diagnostics, including cytogenetics and fluorescence in situ hybridization (FISH) fail to detect MLL translocation partner genes (TPG) in many patients. Long-distance inverse (LDI)-PCR, the “gold standard” technique that is used to characterize MLL breakpoints, is laborious and requires a large input of genomic DNA (gDNA). To overcome the limitations of current techniques, a targeted next-generation sequencing (NGS) approach that requires low RNA input was tested. Anchored multiplex PCR-based enrichment (AMP-E) was used to rapidly identify a broad range of MLL fusions in patient specimens. Libraries generated using Archer FusionPlex Heme and Myeloid panels were sequenced using the Illumina platform. Diagnostic specimens (n = 39) from pediatric leukemia patients were tested with AMP-E and validated by LDI-PCR. In concordance with LDI-PCR, the AMP-E method successfully identified TPGs without prior knowledge. AMP-E identified 10 different MLL fusions in the 39 s les. Only two specimens were discordant AMP-E successfully identified a MLL-MLLT1 fusion where LDI-PCR had failed to determine the breakpoint, whereas a MLL-MLLT3 fusion was not detected by AMP-E due to low expression of the fusion transcript. Sensitivity assays demonstrated that AMP-E can detect MLL-AFF1 in MV4-11 cell dilutions of 10−7 and transcripts down to 0.005 copies/ng. Implications: This study demonstrates a NGS methodology with improved sensitivity compared with current diagnostic methods for MLL-rearranged leukemia. Furthermore, this assay rapidly and reliably identifies MLL partner genes and patient-specific fusion sequences that could be used for monitoring minimal residual disease. Mol Cancer Res 16(2) 279–85. ©2017 AACR.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-05-2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2020
DOI: 10.1200/JCO.19.03117
Abstract: To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial. Patients recruited between 2002 and 2015 with stage 4 disease 1 year or stage 4/4S with MYCN lification 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome. A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patients (9.7%), and nephrectomy was performed in 124 (8.8%). Five-year event-free survival (EFS) ± SE (0.40 ± 0.01) and overall survival (OS 0.45 ± 0.02) were significantly higher with CME compared with IME (5-year EFS, 0.33 ± 0.03 5-year OS, 0.37 ± 0.03 P .001 and P = .004). The cumulative incidence of local progression (CILP) was significantly lower after CME (0.17 ± 0.01) compared with IME (0.30 ± 0.02 P .001). With immunotherapy, outcomes were still superior with CME versus IME (5-year EFS, 0.47 ± 0.02 v 0.39 ± 0.04 P = .038) CILP was 0.14 ± 0.01 after CME and 0.27 ± 0.03 after IME ( P .002). A hazard ratio of 1.3 for EFS associated with IME compared with CME was observed before and after the introduction of immunotherapy ( P = .030 and P = .038). In patients with stage 4 high-risk neuroblastoma who have responded to induction therapy, CME of the primary tumor is associated with improved survival and local control after HDT, local radiotherapy (21 Gy), and immunotherapy.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Wiley
Date: 1996
Abstract: A variety of electrophoretic techniques were used to search for potential causes of human dilated cardiomyopathy (DCM). Northern blots were used to quantify alpha-cardiac and alpha-skeletal muscle actins, and beta-myosin heavy chain mRNAs which are the predominant expressed isoform species. We found a wide range of mRNA levels expressed in both DCM and nondiseased (ND) s les of left ventricles. However, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) gels of the same heart s les revealed a stable and constant ratio of actin and myosin. Dystrophin deficiency might account for the DCM symptoms and so dystrophin levels of DCM and ND s les were evaluated using Western blots probed with monoclonal antibodies for the N-, C- and mid-rod portions of this protein. We found that dystrophin levels were constant in all 29 DCM and 5 ND s les suggesting that dystrophin deficiency is probably not a contributing cause. We explored the possibility that terminal failure may be due to an apoptotic-like event in the cardiomyocytes. Zymograms of DCM and ND s les revealed a significant increase in DNase I activity in the DCM group compared to the ND s les. These data raise the possibility that end-stage failure may be associated with apoptosis.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000207
Abstract: Supplementary Materials and Methods
Publisher: International Microsimulation Association
Date: 30-04-2021
DOI: 10.34196/IJM.00230
Publisher: Informa UK Limited
Date: 09-10-2018
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000204
Abstract: Supplementary Tables S1-S7
Publisher: Wiley
Date: 03-01-2007
DOI: 10.1002/PBC.20795
Abstract: A contemporaneous presentation of a second breast cancer in a mother and an extremity rhabdomyosarcoma (RMS) in her daughter led to the diagnosis of the Li Fraumeni syndrome (LFS). Although the association between LFS and RMS in young patients is well recognised 1 there are no guidelines as to how this knowledge should influence the optimal management of these patients. After reviewing the literature about the natural history of the LFS 2, the incidence of second malignancy (SMN) in RMS survivors 3-6 and the management of extremity RMS 7-9, we are concerned that contemporary RMS treatment, combining non-mutilating surgery with chemoradiotherapy, may be associated with an excessive SMN risk in LFS patients with advanced RMS. We question whether treatment should be in idualised and, where possible and acceptable to the family, measures such as utation should be the considered to attain local control for LFS patients with RMS as this will avoid the need for local radiotherapy without compromising long-term function and quality of life 10.
Publisher: MDPI AG
Date: 19-05-2020
Abstract: Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p 5 × 10−8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p 1 × 10−6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1% p = 3.95 × 10−7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1% p = 4.34 × 10−7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479852
Abstract: Supplementary Figure S1. TERT induces TERT-rearranged neuroblastoma cell proliferation and cell cycle progression through a telomerase-independent mechanism.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/0008-5472.23952251.V1
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530307
Abstract: AbstractPurpose: i TERT /i gene rearrangement with transcriptional superenhancers leads to i TERT /i overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with i TERT /i -rearranged neuroblastoma. Experimental Design: Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with i TERT /i -rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. Results: The BET bromodomain protein BRD4 promoted i TERT /i -rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced i TERT /i -rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with i TERT /i -rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. Conclusions: OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with i TERT /i -rearranged neuroblastoma. /
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.C.6767498.V3
Abstract: Abstract For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed i in vitro /i screening of 125 patient-derived s les against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in i NTRK /i , i BRAF /i , and i ALK /i and responses to matching targeted drugs. The i in vitro /i results were further validated in patient-derived xenograft models i in vivo /i and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers. Significance: Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers. /
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/0008-5472.C.6767498.V2
Abstract: Abstract For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed i in vitro /i screening of 125 patient-derived s les against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in i NTRK /i , i BRAF /i , and i ALK /i and responses to matching targeted drugs. The i in vitro /i results were further validated in patient-derived xenograft models i in vivo /i and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers. Significance: Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers. /
Publisher: Akademiai Kiado Zrt.
Date: 09-2020
Abstract: Alectinib is a central nervous system-active small molecule anaplastic lymphoma kinase (ALK) inhibitor that is effective in the treatment of patients with ALK positive tumors, including advanced non-small cell lung cancers and lymphomas. A simple, isocratic high-performance liquid chromatography–photo diode array detection (HPLC–PDA) assay for measurement of alectinib in human plasma is described. Alectinib is extracted from the plasma matrix by addition of methanol, followed by centrifugation and acidification with 0.1% formic acid. It elutes with a run time of 4.6 min using a 250 mm × 4.6 mm RP-C18 column with 0.1% aqueous formic acid and methanol (35:65, v / v ) and a flow rate of 1 mL/min. Detection was at 339 nm. Linear calibration plots were achieved in the range of 0.1–20 μg/mL for alectinib ( r 2 = 0.9996). With limits of detection and quantification of 0.05 and 0.1 μg/mL, respectively, and excellent precision (%CV 10%), accuracy (bias ±12%), and recovery ( %) within the 1–20 μg/mL concentration range, this assay was suitable for measuring pre-dose alectinib concentrations in an adolescent receiving 600-mg doses twice daily.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000213.V1
Abstract: Supplementary Figures 1-7 and Figure Legends
Publisher: Springer Science and Business Media LLC
Date: 21-05-2013
DOI: 10.1038/BJC.2013.205
Publisher: Wiley
Date: 26-02-2021
DOI: 10.1002/PBC.28922
Abstract: We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B‐cell acute lymphoblastic leukaemia (B‐ALL) and high‐risk genetics, resulting in a minimal residual disease (MRD) response rate of 58%, 2‐year progression‐free survival (PFS) of 39% and 2‐year overall survival of 63%. In total, 83% ( n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab ( n = 12) or following additional salvage therapy ( n = 8). Four patients successfully received CD19‐directed chimeric antigen receptor T‐cell therapy despite prior blinatumomab exposure. Inferior 2‐year PFS was associated with MRD positivity (20%, n = 15) and in KMT2A ‐rearranged infants (15%, n = 9). Our findings highlight that not all children with relapsed/refractory B‐ALL respond to blinatumomab and factors such as blast genotype may affect prognosis.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479849.V1
Abstract: Supplementary Figure S2. BRD4 is required for TERT expression and cell proliferation in TERT-rearranged neuroblastoma cells.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2010
DOI: 10.1038/ONC.2010.332
Abstract: Myc oncoproteins and histone deacetylases (HDACs) modulate gene transcription and enhance cancer cell proliferation, and HDAC inhibitors are among the most promising new classes of anticancer drugs. Here, we show that N-Myc and c-Myc upregulated HDAC2 gene expression in neuroblastoma and pancreatic cancer cells, respectively, which contributed to N-Myc- and c-Myc-induced cell proliferation. Cyclin G2 (CCNG2) was commonly repressed by N-Myc and HDAC2 in neuroblastoma cells and by c-Myc and HDAC2 in pancreatic cancer cells, and could be reactivated by HDAC inhibitors. 5-bromo-2'-deoxyuridine incorporation assays showed that transcriptional repression of CCNG2 was, in part, responsible for N-Myc-, c-Myc- and HDAC2-induced cell proliferation. Dual crosslinking chromatin immunoprecipitation assay demonstrated that N-Myc acted as a transrepressor by recruiting the HDAC2 protein to Sp1-binding sites at the CCNG2 gene core promoter. Moreover, HDAC2 was upregulated, and CCNG2 downregulated, in pre-cancerous and neuroblastoma tissues from N-Myc transgenic mice, and c-Myc overexpression correlated with upregulation of HDAC2 and repression of CCNG2 in tumour tissues from pancreatic cancer patients. Taken together, our data indicate the critical roles of upregulation of HDAC2 and suppression of CCNG2 in Myc-induced oncogenesis, and have significant implications for the application of HDAC inhibitors in the prevention and treatment of Myc-driven cancers.
Publisher: Wiley
Date: 2007
DOI: 10.1002/PBC.20887
Abstract: Lymphoproliferative disease (LPD) is a complication of congenital and acquired immunodeficiency states. There are a number of treatment options for LPD arising after haematopoietic stem cell or solid organ transplantation including reduction of immunosuppression, targeted therapies, such as the anti-CD20 monoclonal antibody, rituximab, and EBV specific cytotoxic lymphocytes. Treatment of LPD in children with congenital immunodeficiency syndromes remains unsatisfactory and is associated with a high mortality rate. We recently managed an infant found to have polymorphic LPD concurrent with X-linked severe combined immunodeficiency (SCID). Haematopoietic stem cell transplantation (HSCT) had to be deferred because of progressive LPD. Treatment with rituximab resulted in regression of the LPD following which the patient received a 5/6 HLA matched umbilical cord blood (UCB) transplant. The patient remains well 20 months following transplantation. Rituximab treatment may have a useful role in the control of LPD associated with congenital immunodeficiency prior to HSCT.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2018
DOI: 10.1007/S11136-018-1788-5
Abstract: Acute lymphoblastic leukemia (ALL) survivors are the largest group of childhood cancer survivors however, their risk for late effects is high. Cancer-related late effects have the potential to compromise health-related quality of life (HRQL) long into survivorship. None of the reviews so far have focused on ALL solely, but described HRQL for all childhood cancers. We aimed to identify ALL survivors at risk for poor HRQL and identify possible risk factors. Following PRISMA guidelines, we performed a systematic review, searching published literature in Pubmed, PsycInfo, Embase, and the Cochrane database including all publications up to December 16, 2016. Two independent reviewers (JV and ER) screened eligible articles and assessed article quality. We found 31 studies representing 4356 survivors and 901 proxies. Thirteen studies found worse, eight found no difference, and three better, overall HRQL scores compared with healthy controls or norms. ALL survivors typically had better overall HRQL scores than survivors of other childhood cancers. Clinical variables (e.g., treatment received) were not consistently associated with HRQL however, experiencing worse late effects was associated with lower HRQL. Survivor and parent socio-demographic factors and psychological factors such as resilience and depression were also associated with HRQL. ALL survivors appeared to have worse or equivalent HRQL compared with controls, but better HRQL than survivors of other cancer types. However, studies reported a wide variability in HRQL and potential risk factors for poor HRQL. Measuring ALL survivors' HRQL longitudinally and comprehensively assessing potential risk factors might identify future avenues to intervene early.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.HLC.2012.04.014
Abstract: Severe acute respiratory distress syndrome (ARDS) in children carries a high morbidity and mortality. High frequency ventilation and extracorporeal membrane oxygenation (ECMO) are used as rescue modes of support in difficult situations. Malignancy may be considered to be a relative contraindication to ECMO support. We report a case where the decision was made to support the patient with ECMO for fulminant Epstein-Barr (EBV) infection while investigations were being done to exclude an underlying malignancy.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2007
Abstract: We retrospectively analysed the outcomes of children transplanted for high-risk neuroblastoma (NB) at a single institution predominantly transplanted with total body irradiation and chemotherapy. The aims of this study were to determine the prognostic impact of clinical and biological features and to document long-term health outcomes. Forty patients were transplanted with a single unpurged autograft. Fourteen patients died from disease progression and two from late complications of treatment. Twenty-three patients are alive at a median of 4.6 years from diagnosis. Kaplan-Meier estimates of overall survival at 2, 5 and 10 years are 76+/-7.0, 60.2+/-8.4 and 54.7+/-9.3% following transplant. Response to induction therapy was significantly associated with survival (P<0.01). Long-term complications included growth (100%) and pubertal failure (83%), hearing impairment (73%), orthopaedic complications (63%), renal impairment (47%) and thyroid abnormalities (36%). Intrinsic and acquired resistance to chemotherapy remains the major obstacle to improving outcomes in high-risk NB. Although patients with chemo-sensitive disease are less likely to experience a relapse, substantial therapy-related toxicities result in poor long-term health outcomes for survivors.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000207.V1
Abstract: Supplementary Materials and Methods
Publisher: Springer Science and Business Media LLC
Date: 09-04-2018
DOI: 10.1038/S41568-018-0003-X
Abstract: Neuroblastoma is a rare solid tumour of infancy and early childhood with a disproportionate contribution to paediatric cancer mortality and morbidity. Combination chemotherapy, radiation therapy and immunotherapy remains the standard approach to treat high-risk disease, with few recurrent, actionable genetic aberrations identified at diagnosis. However, recent studies indicate that actionable aberrations are far more common in relapsed neuroblastoma, possibly as a result of clonal expansion. In addition, although the major validated disease driver, MYCN, is not currently directly targetable, multiple promising approaches to target MYCN indirectly are in development. We propose that clinical trial design needs to be rethought in order to meet the challenge of providing rigorous, evidence-based assessment of these new approaches within a fairly small patient population and that experimental therapies need to be assessed at diagnosis in very-high-risk patients rather than in relapsed and refractory patients.
Publisher: Wiley
Date: 02-2021
DOI: 10.1111/IMJ.14719
Abstract: Cancer therapy related cardiac dysfunction (CTRCD) is an area of increasing focus, particularly during the survivorship period, for paediatric, adolescent and adult cancer survivors. With the advent of immunotherapy and targeted therapy, there is a new set of mechanisms from which paediatric and young adult patients with cancer may suffer cardiovascular injury. Furthermore, cardiovascular disease is the leading cause of morbidity and mortality in the survivorship period. The recently established Australian Cardio-Oncology Registry is the largest and only population-based cardiotoxicity database of paediatric and adolescent and young adult oncology patients in the world, and the first paediatric registry that will document cardiotoxicity caused by chemotherapy and novel targeted therapies using a prospective approach. The database is designed for comprehensive data collection and evaluation of the Australian practice in terms of diagnosis and management of CTRCD. Using the Australian Cardio-Oncology Registry critical clinical information will be collected regarding predisposing factors for the development of CTRCD, the rate of subclinical left ventricular dysfunction and transition to overt heart failure, further research into protectant molecules against cardiac dysfunction and aid in the discovery of which genetic variants predispose to CTRCD. A health economic arm of the study will assess the cost/benefit of both the registry and cardio-oncology clinical implementation. Finally, an imaging arm will establish if exercise cardiac magnetic resonance imaging and VO
Publisher: Springer Science and Business Media LLC
Date: 08-01-2019
DOI: 10.1038/S41375-018-0354-Z
Abstract: Abnormal metabolism is a fundamental hallmark of cancer and represents a therapeutic opportunity, yet its regulation by oncogenes remains poorly understood. Here, we uncover that JMJD1C, a jumonji C (JmjC)-containing H3K9 demethylase, is a critical regulator of aberrant metabolic processes in homeobox A9 (HOXA9)-dependent acute myeloid leukemia (AML). JMJD1C overexpression increases in vivo cell proliferation and tumorigenicity through demethylase-independent upregulation of a glycolytic and oxidative program, which sustains leukemic cell bioenergetics and contributes to an aggressive AML phenotype in vivo. Targeting JMJD1C-mediated metabolism via pharmacologic inhibition of glycolysis and oxidative phosphorylation led to ATP depletion, induced necrosis/apoptosis and decreased tumor growth in vivo in leukemias co-expressing JMJD1C and HOXA9. The anti-metabolic therapy effectively diminished AML stem rogenitor cells and reduced tumor burden in a primary AML patient-derived xenograft. Our data establish a direct link between drug responses and endogenous expression of JMJD1C and HOXA9 in human AML cell line- and patient-derived xenografts. These findings demonstrate a previously unappreciated role for JMJD1C in counteracting adverse metabolic changes and retaining the metabolic integrity during tumorigenesis, which can be exploited therapeutically.
Publisher: Springer Science and Business Media LLC
Date: 06-2022
DOI: 10.1038/S41416-022-01806-6
Abstract: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL -positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1 -deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1 . Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow s les previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 s les, r2 = 0.9786, P 0.0001) and Ig/TCR and IKZF1 -deletion results (9 patients, n = 143 s les, r2 = 0.9661, P 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 s les, r2 = 0.4703, P 0.0001) and IKZF1 -deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P 0.0001). MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1 -deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.
Publisher: Wiley
Date: 13-09-2019
DOI: 10.1111/JPC.14623
Publisher: Wiley
Date: 14-10-2014
DOI: 10.1111/BJH.13142
Abstract: Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment-related mortality of 8%. Leukaemia-free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre-HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre-HSCT (LFS 41%, OS 64%, P < 0·0001) or post-HSCT (LFS 35%, OS 55%, P 50. A Cox multivariate regression model for LFS retained both B-other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post-HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post-HSCT therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000210.V1
Abstract: Supplementary Figures
Publisher: MDPI AG
Date: 28-01-2020
Abstract: To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR) the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients’ eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2–8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN lification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38–47%) and 50% (46–55%) but was 57% (51–62%) and 64% (59–69%) for 378 patients receiving immunotherapy (p 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573) type of HDT (p = 0.0029, HR 1.431) less than complete response prior to maintenance therapy (p = 0.0043, HR 1.494) and metastatic compartment at diagnosis (p 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2020
DOI: 10.1038/S41416-020-0996-2
Abstract: Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. We aimed to identify therapies to prevent and/or treat ALK inhibitor resistance. Malignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts. Xenografts were validated by confirmation of RANBP2-ALK rearrangement, perinuclear ALK localisation and CD30 expression. Although brentuximab-vedotin (BV) demonstrated single-agent activity, tumours regrew during BV therapy. BV resistance was associated with reduced CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse xenograft. CD30 is a therapeutic target in eIMS. BV efficacy is limited by the rapid emergence of resistance. Prolonged survival with combination ALK and CD30-targeted-therapy in the diagnosis model provides the rationale to trial this combination in eIMS patients at diagnosis. This combination could also be considered for other CD30-positive, ALK -rearranged malignancies.
Publisher: Springer Science and Business Media LLC
Date: 16-05-2016
DOI: 10.1038/BMT.2016.122
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000204.V1
Abstract: Supplementary Tables S1-S7
Publisher: Elsevier BV
Date: 05-1993
Abstract: During development of the human heart, the atrial isoform of alkali myosin light chain (MLC1A) is expressed in the ventricle. With maturation of the heart, MLC1A expression is completely replaced by that of the adult ventricular myosin light chain, MLC1V. We have evaluated the re-expression of MLC1A as a marker of different disease states of the human ventricle. RNA was isolated from the ventricles of patients with idiopathic dilated cardiomyopathy (CM) and severe congenital cardiac defects (CCD). Northern blot analysis was used to measure the mRNA levels of MLC1A and MLC1V in these s les. As a control, the level of regulatory MLC2V mRNA was also measured. We find that the level of MLC2V mRNA per microgram total ventricular RNA is very similar in CM, CCD and normal human s les. In contrast, we find that MLC1V mRNA levels tend to be reduced in both CM and CCD s les. In the case of the CCD s les, this apparent drop in MLC1V is compensated by expression of the developmental MLC1A isoform. However, in CM patients in end-stage failure, expression of MLC1A is barely detectable. The expression of MLC1A in CCD s les may reflect an adaptive mechanism in response to cardiac overload. The failure to detect substantial MLC1A expression in the CM s les may reflect the failure of such an adaptive mechanism.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2021
DOI: 10.1158/1078-0432.CCR-20-3044
Abstract: TERT gene rearrangement with transcriptional superenhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma. Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.
Publisher: Public Library of Science (PLoS)
Date: 16-06-2011
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2016
DOI: 10.1158/1078-0432.CCR-15-2717
Abstract: Purpose: We undertook a multidimensional clinical genomics study of children and adolescent young adults with relapsed and refractory cancers to determine the feasibility of genome-guided precision therapy. Experimental Design: Patients with non-central nervous system solid tumors underwent a combination of whole exome sequencing (WES), whole transcriptome sequencing (WTS), and high-density single-nucleotide polymorphism array analysis of the tumor, with WES of matched germline DNA. Clinically actionable alterations were identified as a reportable germline mutation, a diagnosis change, or a somatic event (including a single nucleotide variant, an indel, an lification, a deletion, or a fusion gene), which could be targeted with drugs in existing clinical trials or with FDA-approved drugs. Results: Fifty-nine patients in 20 diagnostic categories were enrolled from 2010 to 2014. Ages ranged from 7 months to 25 years old. Seventy-three percent of the patients had prior chemotherapy, and the tumors from these patients with relapsed or refractory cancers had a higher mutational burden than that reported in the literature. Thirty patients (51% of total) had clinically actionable mutations, of which 24 (41%) had a mutation that was currently targetable in a clinical trial setting, 4 patients (7%) had a change in diagnosis, and 7 patients (12%) had a reportable germline mutation. Conclusions: We found a remarkably high number of clinically actionable mutations in 51% of the patients, and 12% with significant germline mutations. We demonstrated the clinical feasibility of next-generation sequencing in a erse population of relapsed and refractory pediatric solid tumors. Clin Cancer Res 22(15) 3810–20. ©2016 AACR.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.JTHO.2018.08.2020
Abstract: Primary lung cancer is extremely rare in children. It often presents with metastatic disease and carries a poor prognosis. Adenocarcinoma is the most common type of bronchogenic carcinoma in children and adults. Our aim was to systematically review the presenting features, approach to diagnosis and management, as well as the outcomes of primary pediatric adenocarcinoma of the lung. This systematic review was prospectively registered with PROSPERO. The following databases were searched: Medline, Embase, Web of Science, and Scopus for English language cases of primary pediatric adenocarcinoma of the lung. Forty-eight studies were included, comprising 62 patients with adenocarcinoma and 21 cases of adenocarcinoma in situ. Presenting features were nonspecific, with cough and dyspnea the main symptoms at diagnosis. The majority of patients with adenocarcinoma had metastatic disease at diagnosis. Surgery was the most common form of management. More than half the patients with adenocarcinoma had died at final follow-up, whereas 5 of 21 with adenocarcinoma in situ died. Medical management did not improve outcomes, except for two ALK receptor tyrosine kinase (ALK)-rearranged adenocarcinomas that responded to ALK inhibitor therapy alone. Primary pediatric adenocarcinoma of the lung is a rare entity which often presents with metastatic disease and portends a poor prognosis. Surgery is associated with disease-free status, although new agents such as ALK-inhibitors are able to prolong life without surgical management.
Publisher: American Society of Hematology
Date: 20-12-2021
DOI: 10.1182/BLOODADVANCES.2021005576
Abstract: Pediatric regimens have improved outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL). However, results remain inferior to children with ALL. The Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study (anzctr.org.au/ACTRN12611000814976) was designed to assess whether a pediatric ALL regimen (Australian and New Zealand Children’s Haematology and Oncology Group [ANZCHOG] Study 8) could be administered to patients aged 15 to 39 years in a comparable time frame to children as assessed by the proportion of patients completing induction/consolidation and commencing the next phase of therapy (protocol M or high-risk [HR] treatment) by day 94. Minimal residual disease (MRD) response stratified patients to HR treatment and transplantation. From 2012 to 2018, a total of 86 patients were enrolled 82 were eligible. Median age was 22 years (range, 16-38 years). Induction/consolidation was equally deliverable in ALL06 as in Study 8. In ALL06, 41.5% (95% confidence interval [CI], 30.7-52.9) commenced protocol M or HR therapy by day 94 vs 39.3% in Study 8 (P = .77). Median time to protocol M/HR treatment was 96 days (interquartile range, 87.5-103 days) in ALL06 vs 98 days in Study 8 (P = .80). Induction mortality was 3.6%. With a median follow-up of 44 months (1-96 months), estimated 3-year disease-free survival was 72.8% (95% CI, 62.8-82.7), and estimated 3-year overall survival was 74.9% (95% CI, 65.3-84.5). End induction/consolidation MRD negativity rate was 58.6%. Body mass index ≥30 kg/m2 and day 79 MRD positivity were associated with poorer disease-free survival and overall survival. Pediatric therapy was safe and as deliverable in AYA patients as in children with ALL. Intolerance of pediatric ALL induction/consolidation is not a major contributor to inferior outcomes in AYA ALL.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Wiley
Date: 25-12-2020
DOI: 10.1002/PBC.28133
Abstract: The aim of this study was to improve the predictive power of patient-derived xenografts (PDXs, also known as mouse avatars) to more accurately reflect outcomes of clofarabine-based treatment in pediatric acute lymphoblastic leukemia (ALL) patients. Pharmacokinetic (PK) studies were conducted using clofarabine at 3.5 to 15 mg/kg in mice. PDXs were established from relapsed/refractory ALL patients who exhibited good or poor responses to clofarabine. PDX engraftment and response to clofarabine (either as a single agent or in combinations) were assessed based on stringent objective response measures modeled after the clinical setting. In naïve immune-deficient NSG mice, we determined that a clofarabine dose of 3.5 mg/kg resulted in systemic exposures equivalent to those achieved in pediatric ALL patients treated with clofarabine-based regimens. This dose was markedly lower than the doses of clofarabine used in previously reported preclinical studies (typically 30-60 mg/kg) and, when scheduled consistent with the clinical regimen (daily × 5), resulted in 34-fold lower clofarabine exposures. Using a well-tolerated clofarabine/etoposide/cyclophosphamide combination regimen, we then found that the responses of PDXs better reflected the clinical responses of the patients from whom the PDXs were derived. This study has identified an in vivo clofarabine treatment regimen that reflects the clinical responses of relapsed/refractory pediatric ALL patients. This regimen could be used prospectively to identify patients who might benefit from clofarabine-based treatment. Our findings are an important step toward in idualizing prospective patient selection for the use of clofarabine in relapsed/refractory pediatric ALL patients and highlight the need for detailed PK evaluation in murine PDX models.
Start Date: 2018
End Date: 2021
Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: National Health and Medical Research Council
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