Novel strategies to overcome resistance to p53 reactivation in brain tumors

Over 60% of high-grade gliomas (HGGs) retain functional p53 and can benefit from treatment with MDM2 inhibitors.

In the clinical setting, and unlike other cancers, lack of response to MDM2 inhibition is not due to the acquisition of TP53-inactivating mutations.

The aim of this study is to determine mechanisms of resistance to MDM2 inhibition in HGGs, devising strategies to improve the long-term treatment of these tumors.

By using cell-barcoding approaches, I will first determine (Years 1-2) how tumor heterogeneity and cell differentiation state modulate drug response and acquisition of resistance.

I will then interrogate the specific therapeutic vulnerabilities present in the more differentiated population of cells that exhibit tolerance to MDM2 inhibition.

To maximize the effects of drug treatment on HGGs while sparing normal treatment-sensitive tissues, I will next characterize (Years 2-4) baseline levels of apoptotic priming in tumor and normal cells and evaluate the effects of alternative dosing strategies on induction of cell cycle arrest and apoptosis.

With this knowledge, I will finally determine (Years 3-4) whether the use of MDM2 inhibitors in combination with other therapeutic agents can be an effective therapeutic option in HGG.

Given that sustained p53 activation induces senescence in brain tumors, I will specifically test whether combined inhibition of MDM2 and senolytic agents can generate long-term synergistic responses.