Reversing the p53 Mutant Phenotype with a small molecule

Virtually all BRCA1 deficient breast cancers harbor mutations in TP53 suggesting that inactivation of p53 is a requirement for tumor progression. Our group along with the our collaborator, Dr. Shridar Ganesan (Rutgers Cancer Institute of New Jersey) was the first to demonstrate this dependency can be exploited therapeutically using Zinc Metallochaperones (ZMCs) to reactivate mutant p53 (PMID 30993195).  Loss of BRCA1 lead to an amplified activation signal on mutant p53 that enhanced p53 mediated apoptosis.   This has lead us to hypothesize that mutations in other DNA damage response pathway genes (i.e. BRCA2, ATM, ATR) will also render tumors highly sensitive to ZMC therapy.  Although PARP inhibitors (PARPi) have been shown to be effective in the treatment of BRCA1/2 deficient breast, ovarian and pancreatic cancers, acquired resistance is a major clinical problem and there is a pressing need to develop complementary, non-cross resistant therapeutic approaches.  We demonstrated that ZMCs in combination with either PARPi or Bcl-2 inhibitors (Bcl-2i) are highly effective (PMID: 31196889).  We hypothesize these combinations will not only be highly effective in ovarian/breast cancer but also prevent or delay acquired resistance.  This project has been funded by the Breast Cancer Research Foundation continuously since 2014.

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