Mentor Name: Vijay Ramaswamy

Medulloblastoma is the most common malignant brain tumour of childhood, and current treatment consists of surgery, radiation and/or high dose chemotherapy. Despite this treatment, survival for molecularly very high-risk medulloblastoma (infant Group 3, MYC amplified Group 3 and TP53 mutant SHH) remains dismal, with overall survival under 20%. A major limitation to progress has been a lack of actionable targets in the tumour, which preclude an approach to sequence tumours and personalize care. Infants are particularly challenging as the side effects of radiotherapy are devastating necessitating chemotherapy only approaches at the expense of survival. However, the challenge remains that many infants are refractory to current platinum and alkylator based chemotherapy, and ultimately succumb to their disease due to a lack of salvage therapy. A major limitation to progress has been a lack of models to study chemotherapy resistance. To overcome this barrier, Kaitlin will help develop chemotherapy resistant models of very high-risk medulloblastoma, where she will expose four patient-derived stem cell models of MYC amplified Group 3 medulloblastoma to the common chemotherapeutics used in the clinic, and then profile these models to determine what changes are occurring. First the IC50 of three common therapeutics, cisplatin, etoposide and thiotepa will be determine across all four models, followed by exposure at increasing concenrations starting at the IC25 concentration, and doubling the dose every passage. Once she generates the resistant clones, we will profile them with a multi-omic approach of proteomics and transcriptomics. If time permits during the summer, she will also try to re-sensitize the models to chemotherapy using a epigenetic priming, leveraging a high-throughput library of epigenetic modifiers we have in our laboratory. In parallel, Kaitlin will perform a high-throughput drug screen of epigenetic modifiers in combination with these three chemotherapeutics to look for synergistic interactions. Our laboratory has a robust pipeline to conduct high-throughput screening using the HP D300e Digital Dispenser, and we have two large drug libraries of epigenetic modifiers and kinase inhibitors available. As Kaitlin has pre-existing experience with primary cell culture, I anticipate this project is very feasible in a 12 week timeframe, and I anticipate she will be able to create a valuable resource for my laboratory, and more importantly a valuable resource for the medulloblastoma community.