ORCID Profile
0000-0003-0066-6606
Current Organisation
Children's Cancer Institute Australia
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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: 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: 31-07-2023
DOI: 10.1158/0008-5472.23808560.V1
Abstract: Supplementary Figures
Publisher: Cold Spring Harbor Laboratory
Date: 25-07-2023
DOI: 10.1101/2023.07.25.550585
Abstract: To better understand how tumours develop, identify prognostic biomarkers, and find new treatments, researchers have generated vast catalogues of cancer genome data. However, these datasets are complex so interpreting their important features requires specialized computational skills and analytical tools, which presents a significant technical challenge. To address this, we developed CRUX, a platform for exploring genomic data from cancer cohorts. CRUX enables researchers to perform common analyses including cohort comparisons, biomarker discovery, survival analysis, and create visualisations including oncoplots and lollipop charts. CRUX simplifies cancer genome analysis in several ways: (1) it has an easy-to-use graphical interface (2) it enables users to create custom cohorts, as well as analyse precompiled public and private user-created datasets (3) it allows analyses to be run locally to address data privacy concerns (though an online version is also available) and (4) it makes it easy to use additional specialized tools by exporting data in the correct formats. We showcase CRUX’s capabilities with case studies employing different types of cancer genome analysis, demonstrating how it can be used flexibly to generate valuable insights into cancer biology. CRUX is freely available at github.com/CCICB/CRUX and ccicb.shinyapps.io/crux (DOI: 10.5281/zenodo.8015714).
Publisher: Springer Science and Business Media LLC
Date: 15-04-2020
DOI: 10.1186/S12860-020-00268-Z
Abstract: Progesterone receptor membrane component 1 (PGRMC1) is often elevated in cancers, and exists in alternative states of phosphorylation. A motif centered on PGRMC1 Y180 was evolutionarily acquired concurrently with the embryological gastrulation organizer that orchestrates vertebrate tissue differentiation. Here, we show that mutagenic manipulation of PGRMC1 phosphorylation alters cell metabolism, genomic stability, and CpG methylation. Each of several mutants elicited distinct patterns of genomic CpG methylation. Mutation of S57A/Y180/S181A led to increased net hypermethylation, reminiscent of embryonic stem cells. Pathways enrichment analysis suggested modulation of processes related to animal cell differentiation status and tissue identity, as well as cell cycle control and ATM/ATR DNA damage repair regulation. We detected different genomic mutation rates in culture. A companion manuscript shows that these cell states dramatically affect protein abundances, cell and mitochondrial morphology, and glycolytic metabolism. We propose that PGRMC1 phosphorylation status modulates cellular plasticity mechanisms relevant to early embryological tissue differentiation.
Publisher: MDPI AG
Date: 12-10-2020
Abstract: Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived xenograft (PDX) model (TK-RIG915). Patient and PDX tumours were analysed using DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. While initially thought to be a diffuse intrinsic pontine glioma (DIPG) based on disease location, results from methylation profiling and WGS were not consistent with this diagnosis. Furthermore, clustering analyses based on RNA expression suggested the tumours were distinct from primary DIPG. Additional gene expression analysis demonstrated concordance with a published RIG expression profile. Multiple genetic alterations that enhance PI3K/AKT and Ras/Raf/MEK/ERK signalling were discovered in TK-RIG915 including an activating mutation in PIK3CA, upregulation of PDGFRA and AKT2, inactivating mutations in NF1, and a gain-of-function mutation in PTPN11. Additionally, deletion of CDKN2A/B, increased IDH1 expression, and decreased ARID1A expression were observed. Detection of phosphorylated S6, 4EBP1 and ERK via immunohistochemistry confirmed PI3K pathway and ERK activation. Here, we report one of the first PDX models for RIG, which recapitulates the patient disease and is molecularly distinct from primary brain stem glioma. Genetic interrogation of this model has enabled the identification of potential therapeutic vulnerabilities in this currently incurable disease.
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2023
DOI: 10.1158/0008-5472.23808560
Abstract: Supplementary Figures
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 Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000207.V1
Abstract: Supplementary Materials and Methods
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: 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: Cold Spring Harbor Laboratory
Date: 03-11-2020
DOI: 10.1101/MCS.A005710
Abstract: The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase ( NTRK ) family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L–NTRK fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the SPECC1L–NTRK2 fusion directly from a patient s le and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by SPECC1L–NTRK2 expression are sensitive to a TRK inhibitor drug. We report here that SPECC1L–NTRK fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect NTRK fusions, these techniques may be of benefit when NTRK fusions are not suspected on clinical grounds or not identified by other methods.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/0008-5472.23952251
Abstract: Supplementary Figures
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: 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: Springer Science and Business Media LLC
Date: 05-10-2020
Publisher: Research Square Platform LLC
Date: 03-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000210.V1
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000207
Abstract: Supplementary Materials and Methods
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000204.V1
Abstract: Supplementary Tables S1-S7
Publisher: American Association for Cancer Research (AACR)
Date: 21-08-2023
DOI: 10.1158/0008-5472.24000204
Abstract: Supplementary Tables S1-S7
Publisher: Cold Spring Harbor Laboratory
Date: 04-12-2020
DOI: 10.1101/2020.12.03.410860
Abstract: Complex somatic genomic rearrangement and copy number alterations (CNA) are hallmarks of nearly all cancers. Whilst whole genome sequencing (WGS) in principle allows comprehensive profiling of these events, biological and clinical interpretation remains challenging. We have developed LINX, a novel algorithm which allows interpretation of short-read paired-end WGS derived structural variant and CNA data by clustering raw structural variant calls into distinct events, predicting their impact on the local structure of the derivative chromosome, and annotating their functional impact on affected genes. Novel visualisations facilitate further investigation of complex genomic rearrangements. We show that LINX provides insights into a erse range of structural variation events including single and double break-junction events, mobile element insertions, complex shattering and high lification events. We demonstrate that LINX can reliably detect a wide range of pathogenic rearrangements including gene fusions, immunoglobulin enhancer rearrangements, intragenic deletions and duplications. Uniquely, LINX also predicts chained fusions which we demonstrate account for 13% of clinically relevant oncogenic fusions. LINX also reports a class of inactivation events we term homozygous disruptions which may be a driver mutation in up to 8.8% of tumors including frequently affecting PTEN , TP53 and RB1 , and are likely missed by many standard WGS analysis pipelines.
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: 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. /
No related grants have been discovered for Marie Wong-Erasmus.