AS is an aggressive rare sarcoma subtype with a poor long-term outlook for patients with incurable advanced or metastatic disease (< 1 year). Current options are limited with chemotherapy being the mainstay of palliation and other systemic therapies having little durable impact on the disease course. The anticancer drug pazopanib and the therapeutic antibody TRC105 both target the formation and maintenance of blood vessels, and it is from the uncontrolled growth of these blood vessel cells that AS develops. The combination of pazopanib and TRC105 versus treatment with pazopanib alone have recently been assessed in the TAPPAS (TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcomas) clinical trial. Despite being terminated early for futility, there was a subset of patients within this trial who showed durable clinical benefit, suggesting heterogeneity within this disease. Poor understanding of this observed heterogeneity presents a key obstacle to the development of effective ways to stratify AS patients and optimise treatment selection. Research specimens from this largest trial in AS offer an unprecedented opportunity to address these challenges.
The objective of this project is to perform translational studies comprising deep molecular analysis of tissue specimens and blood samples from TAPPAS. The student will uncover the biological and immunological features that can predict which are the AS patients most likely to benefit from drug treatment. Such a predictive tool will help doctors administer these drugs to the right patients while sparing those patients who are unlikely to benefit from unnecessary side effects. We will also determine if liquid biopsies can be used to monitor early treatment response in a non-invasive manner which would minimise the need for tissue biopsies. We anticipate that this research will accelerate the discovery of innovative biomarkers for patient stratification and uncover therapeutic opportunities which will ultimately improve patient outcomes.
The project is composed of 3 aims. Aim 1: Define candidate molecular mechanisms of pazopanib and TRC105 resistance and sensitivity in AS using state-of-the-art molecular profiling approaches. Aim 2: Develop liquid biopsies for monitoring therapy response and disease relapse using serial blood samples from the TAPPAS trial, including circulating and cytokine analysis. Aim 3: Characterise the tumour immune microenvironment in AS specimens from the TAPPAS trial using multi-spectral immunofluorescence
Training and development
The PhD student will be supervised by Dr Paul Huang in the Division of Molecular Pathology and will benefit from mentorship and training in multi-disciplinary team. There will be a close collaboration with the Chief Investigator of the TAPPAS trial Prof Robin Jones, Head of the Sarcoma Unit at the Royal Marsden. The student will be trained in state-of-the-art Omic profiling strategies as well as liquid biopsy analysis techniques. The student will be exposed to Translational research, Sarcoma Molecular Pathology, Cancer Biology, Signal Transduction and Systems Pharmacology.
Keywords /Subject Areas
Cancer biology
Translational research
Cancer therapeutics
Rare cancers
Biomarkers
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