Studying Anti-MDM2 PROTAC May Yield New Modality in p53-Mutated Cancer

In a conversation with CancerNetwork^® at the 7th International Li-Fraumeni Syndrome (LFS) Association Symposium, Christine M. Eischen, PhD, discussed her work focusing on the development of a novel precision therapy for patients with p53-mutated cancer.

Eischen is a Herbert A. Rosenthal, MD ‘56 Professor of Cancer Research and founder and co-director of the Blood Cancer Center of Excellence at Sidney Kimmel Cancer Center of Thomas Jefferson University.

In a presentation at the symposium, Eischen highlighted ongoing efforts to develop an anti-MDM2 proteolysis-targeting chimera (PROTAC) that can activate the p73 gene, which may consequently yield apoptosis of cancer cells in patients with p53-mutated disease. According to Eischen, more work is necessary to further optimize the MDM2-targeted PROTAC prior to potentially enrolling patients on a clinical trial to assess the hypothesis that the agent may extend the survival of those with p53-mutated cancers.

Transcript:

If we hit MDM2 and cause its degradation with a proteolysis-targeting chimera, what results is cellular stress that can activate a p53 family member called p73, and that has many of the same targets. [This] means it overlaps with the targets that p53 has. The transcriptional target, specifically, will upregulate genes that will then lead to form of cell death called apoptosis.

Once we have a [PROTAC] that is more optimized, we could get into [recruiting patients] for a clinical trial. The hypothesis, then, is that this would result in significant killing of their p53-mutant cancers and therefore extend their survival. It would be a new treatment modality.

The next steps are to optimize the MDM2 PROTAC so we can give it to [patients] for clinical trials. That is one of the big [next steps]. [We must] then understand more mechanisms of how it is killing [cancer cells] because other mechanisms may be involved in this that could contribute to the specifically targeted death of the cancer cells that have mutant p53 or deleted p53.

Reference

Eischen CM. Precision targeting of p53 mutant cancers. Presented at the 7th International Li-Fraumeni Syndrome (LFS) Association Symposium; October 19-22, 2024; Philadelphia, PA.