Functional Analysis of p53 Polymorphic Variants - Diversity Supplement

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Project Summary This is a request for Supplement to R01 CA102184 to train Ms. Maya Foster, a highly talented graduate student at the University of Pennsylvania to train with Dr. Maureen Murphy at The Wistar Institute to study a newly discovered compound called SM26.1 that binds to mutant p53 and stabilizes this protein in a wild type conformation. This research is related to the parent R01, which recently uncovered that two different germline variants of the p53 tumor suppressor gene, P47S (Pro47Ser) and Y107H (Tyr107His) have the potential to misfold into a mutant conformation and hence contribute to increased cancer risk in humans and mice. These findings led to Maya’s idea to see whether compounds uncovered in the lab of our collaborator, John Karanicolas at Fox Chase Cancer Center, had the potential to ‘refold’ mutant p53, including the P47S and Y107H variants, into a wild type conformation. In the research described, Maya will engage in a vibrant and collegial environment at The Wistar Institute, and take part in long-standing collaborations of the Murphy lab with the George and Maxwell labs at Penn, and the Karanicolas lab at Fox Chase. For her research project, Maya has selected to focus on ovarian cancer, with the knowledge that this tumor type mutates p53 100% of the time, and has poor prognosis and is in urgent need of new therapies. The decision to focus on ovarian cancer allows Maya to take part in our meetings for a planned P01 in ovarian cancer, which includes clinicians from Penn and Investigators from Wistar, Penn, Fox Chase Cancer Center and Thomas Jefferson University, in monthly meetings held at The Wistar Institute. The two aims of this proposal will identify the mechanism of action, and therapeutic efficacy, of this novel p53 refolding compound.