Field of Research (FoR)
I am a clinician scientist, with 25 years experience as a consultant paediatrician and oncology research. I am appointed at the Children’s Cancer Institute, to lead the Translational Tumour Biology group, and cross-appointed at the Peter MacCallum Cancer Centre and Murdoch Children’s Research Institute (MCRI) to drive collaborative projects that link basic research with the discovery of novel therapeutic targets and genetic understanding...view more
I am a clinician scientist, with 25 years experience as a consultant paediatrician and oncology research. I am appointed at the Children’s Cancer Institute, to lead the Translational Tumour Biology group, and cross-appointed at the Peter MacCallum Cancer Centre and Murdoch Children’s Research Institute (MCRI) to drive collaborative projects that link basic research with the discovery of novel therapeutic targets and genetic understanding of paediatric cancers.
In 2014 I was appointed as Group Leader of Cancer Research at The Murdoch Children’s Research Institute. I built a new molecular cancer research program linked to the clinical service, with 2 overarching aims. The first was to establish a research program of RNA sequencing of patient samples, focused primarily but not exclusively, on childhood Acute lymphoblastic Leukaemia. I used RNA-sequencing as a tool to discover the driving genetic lesions, which were then modelled to explore their biology. The second aim was, as a lead investigator in the national and local initiatives in paediatric personalised medicine, to make these precision medicine trials available to the paediatric cancer population, and to expand our research portfolio to encompass cancer genomics in paediatric oncology.
In 2019 I took up a role as a Group Leader at the Children’s Cancer Institute (CCI), with cross-appointments at the Peter MacCallum Cancer and Murdoch Children’s Research Institute. I lead the Translational Tumour Biology group which explores the molecular biology and therapeutic targeting of genomic discoveries from the Zero Childhood Cancer patient cohort – the national child cancer personalized medicine program. This involves the development of models to investigate the functional molecular consequences of the genetic changes found in the patients, and to determine how they might best be therapeutically targeted.
MB.BS, PhD, FRACP, FFS(Research)(RCPA)
My Research Activities
My research explores the basic biology of oncogenic lesions that drive paediatric cancer. Our goal is to generate model systems with which we can explore the functional molecular basis of cancer-related mutations, and to identify better targeted ways to treat these. Our work intersects directly with the genomic findings for the Zero Childhood Cancer national clinical trial. This project is open and recruiting from all paediatric cancer clinical services and is the largest clinical trial of “precision medicine” in paediatric cancer in Australia. This study is led from the Children’s Cancer Institute (NSW). This project recruits children with relapsed or difficult to treat malignancies and undertakes a full genomic analysis (RNA-sequencing and Whole Genome Sequencing) of the tumours, in vitro drug screening and the establishment of in vivo PDX models where possible. My Translational Tumour Biology Group takes novel findings from these patients to explore their basic biology in model systems in the laboratory.
We have several areas of particular interest.
1. Fusion oncogenes. Structural variants that result in expression of gene fusions are frequent drivers in paediatric cancer. Typically, these events drive aberrant expression of specific domains of the genes involved, such as tyrosine kinase domains. We are discovering many new oncogenic fusions in childhood cancer about which little is known of the molecular basis of their oncogenic effects, and how they might be therapeutically targeted. We use the tools of molecular and cellular biology, and genomic analyses to explore these new cancer drivers. We have a particular interest in how fusion oncogenes regulate molecular cell death pathways.
2. Functional Genomics. We use functional genomics methodologies to study the roles of genes in childhood cancers. This includes using functional genomics to undertake screens and to generate new cancer models. We want to define the specific oncogenic pathways that are activated in childhood malignancies, use genomics, such as gene expression profiles, to prospectively recognise activation in patient samples. The aim is to use this molecular knowledge to advance more targeted cancer therapies. A new and exciting project is exploring how we can use Cas13 to specifically regulate the expression of oncogenic fusions and gene mutations.
3. Immunology of High-risk Paediatric Cancer. We have a major collaboration with the Pater MacCallum Cancer Centre in Melbourne to comprehensively profile the immune microenvironment of high-risk paediatric cancers. We want to understand the mechanisms by which some tumours can escape immune-mediated clearance, and predict which paediatric caners may best respond to immune-based therapies.
My Research Supervision
Areas of supervision
The Translational Tumour Biology Group is keen to offer exciting and interesting projects for HDR Candidates. There are a number of potential research projects that may interest students. The common theme of each is the study of the molecular biology of cancer drivers identified in the tumour samples of patients recruited to the Zero Childhood Cancer Program. In some cases these drivers have been previously identified, but the molecular details of their function are not known. In other cases, we have identified new classes of cancer driving variants. In these cases the goal is to develop new models and investigate the molecular functions. The ultimate goals are to find ways to therapeutically target these genomic lesions, based on a detailed appreciation of their biology.
The Molecular Functions of Paediatric Fusion Oncogenes. We have identified several novel oncogenic drivers in a range of paediatric cancers. Some of these activate signalling pathways through the aberrant expression of kinase domains. Others appear to regulate differentiation by driving expression of homeobox domains. The goal of these projects is to understand the molecular basis of the oncogenic function of these fusion genes. The oncogenes are sequenced and cloned from patient samples, and expressed using a range of model systems. The tools of biochemistry and molecular biology are used to understand their biology. This includes advanced genomic techniques to understand where some fusions locate in the genome, how they function to regulate the expression of other genes, explore gene interactions and dependencies, and how the fusion genes can be therapeutically targeted.
Kinase Activation in Paediatric Sarcoma. This is a collaborative project with Dr Emmy Fleuren of the Children’s Cancer Institute. This project uses advanced proteomics techniques to dissect the phosphoproteome of paediatric sarcoma subtypes. The phosphoproteome provides a unique insight into the activation of certain signalling pathways in cancer cells. Further, these pathways can be targeted by kinase-inhibitor drugs. This project aims to understand what kinase signalling pathways are active in sarcoma, how they become active, and what drugs can be used to switch off the pathways.
Immune Landscape of High-Risk Paediatric Cancer. This project uses both genomic and histological features to understand the immune microenvironment of childhood cancer. The project has several potential lines of investigation, from characterising the immune micro-environment to development model systems to test potential immunotherapies. The project is being done in collaboration with the Peter MacCallum Cancer Centre in Melbourne, and among the techniques employed is advanced microscopy methods such as multiplex immunohistochemistry and CyTOF.