Research Supervisor Connect
Brain tumours are the leading cause of cancer-related death and most common solid tumour type in children. Paediatric brain tumours present as a broad spectrum of pathologic and molecular entities requiring precise diagnosis and treatment. Despite advances in molecular diagnostics and therapeutic approaches, the prognosis for many children with brain tumours remains poor, especially for those with diffuse high-grade gliomas (HGG), where 70-90% die within 1-2 years of diagnosis. Survivors often endure long-term sequelae caused by the toxicity of their cancer treatment. New treatments that specifically target molecular abnormalities responsible for these cancers, while sparing normal cells, are urgently needed to address these issues.
This project will provide a critical path forward in the development of new therapeutic approaches to the treatment of paediatric HGG through targeting cancer cell immortality, i.e. the ability of cancer cells to proliferate relentlessly without normal limitations.
Cancer cell immortality develops as a direct result of activation of mechanisms that lengthen specialised structures at the ends of chromosomes called telomeres. Since telomere lengthening mechanisms (TLM) do not operate in most normal cells, their activation in cancer cells presents a vulnerability ideal for therapeutic exploitation. The currently proposed study will apply recent discoveries made in our lab from a large pan-cancer study of telomere biology in 976 cancer models to prioritise new diagnostic biomarkers, therapeutic targets and drug repurposing opportunities in the development of new treatments for paediatric HGG. The overall goal is to improve outcomes for children with HGG by expanding precision medicine to include new molecularly-targeted therapeutic strategies that exploit mechanisms underlying cancer cell immortality.
Westmead - Childrens Medical Research Institute
This project will utilize patient-derived cell lines representing different types of paediatric brain tumours, along with associated multi-omic data to investigate the potential for exploiting telomere biology-related biomarkers, molecular targets and experimental therapeutics in the treatment of paediatric brain cancers. Cancer cells most frequently employ one of two well-known TLM: the enzyme telomerase, or the Alternative Lengthening of Telomeres, which depends on DNA recombination between chromosome ends. Promising new therapeutics that target each of these mechanisms are currently in development.
The first aim of this project is to develop an accurate and clinically applicable molecular diagnostic approach to stratify patients based on TLM. Toward this goal, comprehensive characterisation of each sample, through TLM assays and mass spectrometric analysis of protein content using clinically applicable technology developed by our team, is already underway. Once this dataset is generated, bioinformatic tools will be applied to test the biomarkers and molecular classifiers from our pan cancer study for TLM accuracy prediction. Using machine learning approaches, the classifiers will be refined to ensure accuracy for diagnostic stratification of paediatric brain tumours according to TLM. We will then test HGG patient-derived cell lines for sensitivity to known TLM-targeted therapeutics and apply gene knockdown and knockout approaches to test the utility of molecular targets in these cell lines. Combination targeting strategies will also be investigated. Collectively, the results will provide new directions for developing new treatment strategies for children with aggressive brain tumours, such as HGG.
We welcome enquiries from potential PhD candidates with passion and ambition for a career in cancer research.
This research project will be undertaken within the Cancer Research Unit at the Children’s Medical Research Institute. More information about our research and team can be found here.
Prospective students can find information on CMRI scholarship opportunities here.
The opportunity ID for this research opportunity is 3562