Therapeutic Reactivation of p53 to Overcome Apoptotic Resistance in Pediatric Leukemia
p53 is a renowned tumor suppressor gene that is frequently mutated or deleted in cancer, resulting in the development, persistence, and chemoresistance of human cancers. In surveying the broad spectrum of cancers for genetic modification of p53, we have identified a series of pediatric leukemias that maintain expression of wild-type p53 despite the attendant risks to tumor cell survival. We hypothesized that mechanisms other than p53 mutation and deletion could be operational to neutralize p53 activity in these contexts, including negative regulation of p53 by HDM2 and/or HDMX. We have developed the first and only dual inhibitor of HDM2 and HDMX, and demonstrated in proof-of-concept experiments that our compound can overcome chemoresistance in HDMX-dependent solid tumors. Based on these data, an optimized version of our drug has now advanced to Phase I clinical trials in relapsed adult solid tumors that maintain wild-type p53 expression. Here, we propose to investigate whether dual targeting of HDM2 and HDMX can serve as a novel therapeutic strategy for reactivating p53 in primary and relapsed pediatric leukemias, and thereby provide a rationale for expanding such clinical trials to include pediatric leukemia patients.
