Abstract 1766: Investigating Chk1 biology with selective oral Chk1 inhibitor.

Abstract Chk1 inhibitor as a chemo-potentiator in cancer therapy was proposed more than 10 years ago. Most of the first generation i.v. dosing chk1 inhibitors were terminated in clinical trials recently. The second generation oral chk1 inhibitors were just launched by several companies. However, many questions in Chk1 biology remain unclear, which is important to guide Pfizer to develop oral chk1 inhibitor in the future. Chk1 biology team investigated preclinical scheduling, biomarker, combination strategy, TGI, primary indication and patient selection with chk1 tool compounds. Biomarker is critical in evaluating POM in clinical trial phase I. Significant target modulations and dose responses of biomarkers p-Chk1 345, r-H2AX, cleaved-PARP were observed in both in vitro and in vivo studies, suggesting their potential application in clinical setting. The scheduling study indicated its importance in chk1 project. Both administration of chk1 inhibitor soon after chemotherapy and sustained inhibition of chk1 robustly improved efficacy in Miapaca2 pancreatic cancer model. There was no clear patient selection strategy for Chk1 clinical trials in the past. To investigate the primary indication and patient selection, 6 indications were indentified according to clinical trial results and human tumor tissue genomics, more than 100 cancer cell lines were screened with either chk1 inhibitor alone or in combination with SOC. 75%(12/16) cell lines in mesothelioma and 44% (4/9) in endometrial carcinoma demonstrated significant synergy in the combination treatment. Next generation sequencing and SiRNA library screening in DNA damage repair genes (DDR) will be used to clarify the mechanisms. In summary, we have identified treatment schedule and potential new indications for Chk1 inhibitor, which could significantly increase efficacy, lower toxicity, and improve probability of success in clinical trials. Citation Format: Zhenxiong Wang. Investigating Chk1 biology with selective oral Chk1 inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1766. doi:10.1158/1538-7445.AM2013-1766