Research Supervisor Connect
The survival of patients with rare cancers is disproportionately low (58.5%) compared to patients with more common cancers (76.5%). Precision medicine has the potential to improve outcomes of patients with rare cancers by delivering personalised treatment targeting specific molecular abnormalities detected in the individual’s cancer. However, an estimated 50% of patients referred to precision medicine programs do not receive personalised treatment because molecular testing fails to identify abnormalities that match the currently available molecular-targeted therapeutics. New molecular-targeted therapies are urgently needed to bridge this gap.
This project will provide a critical path forward in the development of new therapeutic approaches that target a fundamental property of almost all cancer types: the ability of cancer cells to replicate without limit (cancer cell immortality).
Cancer cell immortality results from the activation of mechanisms that prevent shortening of chromosome ends (telomeres). This study will focus on cancers that activate a specific type of telomere length maintenance mechanism referred to as Alternative Lengthening of Telomeres (ALT). ALT is estimated to occur in 10% of all cancers and is disproportionately detected in cancers that are biologically aggressive and have limited therapeutic options. ALT-dependent cancers are over-represented among rare cancer types that mostly affect young patients, such as sarcomas and paediatric brain tumours, but ALT also occurs in cancers associated with aging such as pancreatic neuroendocrine tumours.
This study will identify and prioritise drug targets and diagnostic biomarkers in ALT cancers from diverse tumour types to enable development of new treatments for incorporation into precision medicine. An additional outcome of this study will be provision of a large dataset of molecular information that will be an exceptional resource for other researchers working on a group of rare cancers that have been understudied and therefore have unmet therapeutic need.
Westmead - Childrens Medical Research Institute
New molecular-targeted therapies are needed for the substantial portion of cancer patients who currently do not benefit from precision medicine due to a lack of identifiable targetable mutations or molecular abnormalities. Telomere length maintenance mechanisms (TMM) are activated in most cancers to enable replicative immortality and have unrealised potential for therapeutic exploitation. The objective of this project is to prioritise molecular targets and biomarkers for development as therapeutics and companion diagnostics for aggressive cancers that utilise the Alternative Lengthening of Telomeres (ALT) mechanism. The investigations will leverage a pan-cancer dataset of TMM metrics and proteomic data of unprecedented depth and breadth that we have recently generated.
Hypothesis: Activation of ALT creates an “Achilles heel” of molecular vulnerabilities that can be exploited to develop targeted cancer therapeutics.
Aim 1: Characterisation of novel TMM states using cancer models for subclonal, single cell and drug sensitivity analysis.
Aim 2: TMM characterisation of a multi-cancer validation cohort of patient samples and independent cancer models (testing ALT biomarkers and therapeutic targets.
Aim 3: Functional validation of novel therapeutic targets in models of ALT-related cancers.
The outcomes of this study will prioritise ALT-associated molecular vulnerabilities and biomarkers for therapeutic development. It will also characterise novel TMM states that may otherwise confound biomarker-directed precision medicine with TMM-targeted therapies. Completion of this study will provide a critical path forward for addressing the unmet therapeutic need of patients with rare and aggressive cancers addicted to ALT.
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 3561