Abstract P6-20-05: Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation

Abstract

Abstract Triple negative breast cancer (TNBC) is an aggressive subset for which novel therapeutic approaches are needed. A significant proportion of TNBC patients harbor either germline or somatic mutations in BRCA1, or epigenetic silencing of BRCA1, which renders them deficient in DNA repair. Virtually all BRCA1 deficient breast cancers harbor mutations in TP53 suggesting that inactivation of p53 is a requirement for tumor progression in the setting of BRCA1 deficiency. Due to this dependency, we hypothesized that restoring wild type p53 function in BRCA1 deficient breast cancer would be therapeutic. The majority of TP53 mutations are missense, which generate a defective protein that potentially can be targeted with small molecules. Zinc Metallochaperones (ZMCs) are a new class of anti-cancer drugs that reactivate a class of zinc deficient mutant TP53 alleles by restoring zinc binding. Using ZMC1 in human breast cancer cell lines expressing the zinc deficient p53R175H, we demonstrate that loss of BRCA1 sensitizes cells to mutant p53 reactivation. Using genetically engineered murine mammary tumor models with Brca1 deficiency, we demonstrate that ZMC1 significantly improves survival in mice bearing tumors harboring the zinc deficient Trp53R172H allele but not the Trp53 null allele. We synthesized a novel formulation of ZMC1 (Zn-1), in which the drug is made in complex with zinc to improve zinc delivery, and demonstrate that Zn-1 has increased efficacy over ZMC1. Furthermore, we show that ZMC1 plus olaparib is a highly effective combination for tumors expressing the p53R172H mutant. In conclusion, we have validated preclinically a novel therapeutic approach for BRCA1 deficient breast cancer through reactivation of mutant p53. Citation Format: Na B, Yu X, Wither T, Gilleran J, Yao M, Foo TK, Chen C, Moore D, Xia B, Lin Y, Kimball D, Ganesan S, Carpizo D. Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-05.