Reactivation of p53-Mediated Apoptosis in Neuroblastoma
The Walensky laboratory has found that a subset of neuroblastomas have a distinct protein expression signature that may render them susceptible to a new treatment strategy. Certain neuroblastomas retain the expression of the wild-type form of p53, a critical regulator of genome integrity, the cell cycle and cell death. Although p53 is a tumor suppressor and a risk to these neuroblastoma cells, two negative regulator proteins, HDM2 and HDMX, block the functional activity of p53, rendering it ineffective. Dr. Walensky's group has developed “stapled peptides” modeled after a single alpha-helix of p53 that directly binds to HDM2 and HDMX. When administered to cells, the stapled p53 peptide can neutralize HDM2 and HDMX and reactivate the tumor suppressor activity of p53. The benefits of this targeting strategy have driven its advancement to ongoing clinical trials in adults.
For my summer project, I will be testing the effect of a lead stapled p53 peptide on a series of neuroblastoma cells. I will evaluate p53, HDM2 and HDMX levels by western analysis and measure the effect of treatment on cell viability in those cells that either maintain wild-type p53 expression, have mutated or have deleted it. I will also measure the increase of p53 and its transcriptional target, p21, over time. By working on a project that blends chemistry, cancer biology and therapeutic efficacy testing, I hope to gain new insight into the complete arc of cancer discovery and also participate in translating a new treatment strategy for neuroblastoma.