A multidisciplinary approach to target MYC-driven childhood cancers
Prof E Tate
Prof L Chesler
Friday, November 22, 2019
Funded PhD Project (European/UK Students Only)
Synthetic lethality driven by N-myristoyltransferase inhibition: a convergence approach to target MYCN-driven childhood cancers
Short title: A multidisciplinary approach to target MYC-driven childhood cancers
Project Description Aberrant expression, mutation or amplification of the key transcription factor and oncogene MYC, and its neural homologue MYCN, defines 20% of poor-outcome adult and childhood cancers, making MYC an important, but undrugged cancer target. Aberrant MYC activity is a known driver of poor clinical outcome and resistance to chemotherapy in significant subsets of children with brain and solid tumours (glioblastoma, medulloblastoma, rhabdomyosarcoma and neuroblastoma). These tumours remain a treatment challenge and collectively account for a majority of annual deaths from cancer in children. Paediatric cancer is a highest-priority area for Cancer Research UK support under the CRUK Kids & Teens strategy, linking leading paediatric cancer scientists with investigators expert in drug discovery and development.
Our labs have made the exciting discovery that oncogenic expression of MYC/MYCN exposes a novel druggable vulnerability which can be targeted with potent and selective inhibitors of specific protein posttranslational modification (PTM) pathways. Furthermore, the Tate lab has developed a platform of chemical probe technology uniquely capable of unlocking novel mechanisms of action in protein PTM pathways, along with extremely potent and selective inhibitors of these pathways, whilst the Chesler lab has established the in vitro and in vivo models required to unpick the complex biology underlying MYCN-dependency.
As the student on this project you will be at the centre of a multidisciplinary collaboration to understand the mode of action of inhibitors targeting PTM pathways in MYCN-driven childhood cancers, with additional broad applications in a range of MYC-driven cancers. You will apply chemical proteomic tools and novel drugs currently in preclinical development to drive validation of drug targets in these pathways. Your research work will be based between the lead supervisors’ labs at the state-of-the-art Molecular Sciences Research Hub at Imperial’s White City campus, the Francis Crick Institute, and Centre for Paediatric Experimental Medicine at the Institute of Cancer Research. You will also interact with scientists at Myricx Pharma, a drug discovery spinout from Imperial College and the Francis Crick Institute focused on preclinical development of PTM pathway inhibitors in cancer. You will receive training in all relevant aspects of chemical biology, proteomics, cancer cell biology and in vivo models. You will also benefit from membership of the joint ICR/Imperial Cancer Research UK Convergence Science Centre.
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Convergence Science PhDs cover tuition fees for UK/EU students only.