Achuth Padmanabhan, PhD
Baylor College of Medicine
2019 Skacel Family Scholar
PROTAC-mediated degradation of oncogenic gain-of-function p53 mutants: A personalized therapeutic strategy for ovarian cancer
Ovarian cancer is the fifth leading cause for cancer-associated deaths among women in the US and is associated with frequent mutations in p53 gene. While some mutations result in the loss of function of the p53 protein, several mutations in the gene result in a mutant protein that gains new functions which promote the growth of the tumor. These gain-of-function p53 mutant proteins help the cancer cells become more aggressive and resistant to chemotherapy. These tumor promoting gain-of-function p53 proteins form very stable aggregates or clusters that accumulate to high levels in cancer cells. Depletion of these mutant p53 proteins in ovarian cancer cells causes the cells to die suggesting that cancer cells need these mutant proteins to survive. Thus, depleting these mutant proteins from cancer cells provides a potential therapeutic opportunity. However, achieving selective depletion of mutant p53 proteins in ovarian cancer cells in a way that can be applied in the clinic has been extremely challenging. In this study, Dr. Padmanabhan proposes to overcome this challenge by developing a novel strategy to selectively deplete gain-of-function mutant p53 proteins in ovarian cancer cells thereby causing cancer cell death. Dr. Padmanabhan will use state of the art chemistry technology to develop Protein Targeting Chimera (PROTAC) to specifically bind mutant p53 to kill ovarian cancer cells implanted in mice. If successful, this project would help pave the way for a personalized and targeted approach for treating ovarian cancer.