Abstract 2624: Pre-clinical studies of a mutant p53 reactivating drug in pancreatic cancer

Abstract

Abstract Pancreatic cancer therapy suffers from a lack of effective chemotherapy. TP53 is second only to Kras as the most commonly mutated gene in pancreatic cancer with point mutations occurring in 75% of patients. Recently, our laboratory identified ZMC1 as an allele specific p53 mutant reactivating compound. This compound selectively kills cancer cells that express the p53-R175H mutation by restoring wildtype structure and function to this mutant. It does not reactivate the DNA contact mutant, p53-R273H or p53-R248H. This established ZMC1 as a lead compound for mutant p53 targeted drug development. We are currently investigating the potential of ZMC1 as novel anti-cancer drug through pre-clinical studies in pancreatic cancer. Previously we reported the ZMC1 allele specificity in murine pancreatic cancer cell lines derived from the KPC mouse model expressing mutant KrasG12D and different alleles of TP53 (WT, null, p53R172H, p53R270H). We have investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of ZMC1 in the KPC mouse model. Using LC/MS/MS we developed a sensitive assay for detection of ZMC1 in mouse plasma. We measured drug concentrations in mouse plasma and tumor tissues in different delivery routes and different dosages in the PK studies. We have developed a PD assay for ZMC1 with cleaved caspase-3 immunostaining with which we have tested several doses of ZMC1 and found that we detect activity of ZMC1 in KPCp53-R172H xenograft tumors while at the same time relatively no activity in KPCp53-R270H tumors. These same assays were also performed on KPC autochthanous tumors and again revealed activity of ZMC1 in the KPCp53-R172H mice. Efficacy studies in the KPCp53-R172H xenografts showed potent tumor growth inhibition at both intravenous (1mg/kg) and intraperitoneal (5mg/kg) dosing while no evidence of growth inhibition in KPCp53-R270H. Furthermore, ZMC1 extended the survival days from average 15 days to 26 days in the KPCp53-R172H mice but it was not significantly observed in the KPCp53-R270H mice. The tumor growth rate was also decreased in the KPCp53-R172H but not in the KPCp53-R270H mice. These studies indicated that ZMC1 is an allele-specific p53 mutant reactivating compound and holds promise for future applications in pancreatic cancer. Citation Format: Xin Yu, Ashley T. Tsang, Zhe Li, Oliver S. Eng, Hongxia Lin, Murugesan Gounder, Darren R. Carpizo. Pre-clinical studies of a mutant p53 reactivating drug in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2624. doi:10.1158/1538-7445.AM2015-2624