Unravelling the mechanisms and therapeutic opportunities of mutant p53 gain-of-function mediating tumor immune evasion

p53 as a major tumor suppressor which inactivation is required for tumor development. This inspires the idea of p53 reactivation to combat cancer.

The mutant p53-reactivating compound PRIMA1MET/APR-246 which we discovered has obtained Fast Track and Breakthrough Therapy designation by FDA and is currently being tested in several Phase II clinical trials.

With the advent of immune anti-cancer therapy it becomes imperative to understand how immune checkpoints are affected by novel target-specific drugs.

In this project we will capitalize on our recent discovery that p53 can boost anticancer immune response via trigerring interferon (IFN) pathway.

We aim to find out whether and how mutant p53 is involved in the regulation of IFNs, thereby promoting inflamed tumor microenvironment.

We will identify the molecular mechanisms of the newly discovered gain-of-function mutant p53 properties affecting immune cancer surveillance in vitro, ex vivo, in vivo and in patient samples using modern molecular biology and highthroughput approaches.

We will find out whether restoration of mutant p53 function by APR-246 can boost the IFN response, regulate immune checkpoints, promote immune cell infiltration and  synergize with immune checkpoint therapy using mouse models.

I envisage that this innovative program will promote clinical trials of p53-targeting therapies and will help to stratify patient cohorts, allowing personalized cancer medicines for the benefit of patients.