Dissecting and Targeting Apoptotic Resistance in Pediatric Leukemia
Mentor: Loren Walensky
Relapsed and refractory pediatric cancer is driven by apoptotic resistance or the inability of tumor cells to die even in response to formidable treatment. The BCL-2 family of apoptotic regulators control the critical balance between cellular life and death and cancer cells usurp the survival arm of this family to enforce cancer cell immortality. The founding member of the family, BCL-2, is overexpressed in a series of pediatric leukemias and is a critical contributor to apoptotic resistance. Venetoclax, a selective small molecule inhibitor of BCL-2 can be an effective drug for BCL-2 dependent pediatric leukemias, but mutant protein variants have already emerged that thwart this treatment. Given the importance of BCL-2 as a therapeutic target in pediatric cancer, alternative drug strategies are required. The Walensky laboratory has pioneered the development of structured peptides that recapitulate the natural shape of helical motifs involved in protein-protein interactions. For my POST project, I will deploy a library of stapled peptides to identify potent and selective BCL-2 inhibitors that overcome venetoclax resistance. I will apply biochemical, structural, and cellular approaches to advance lead compounds that reactivate the apoptotic pathway in order to overcome treatment-resistance in pediatric leukemias.