Abstract 3448: Strong synergistic effects with cisplatin and APR-246, a novel compound reactivating mutant p53, in ovarian cancer cell lines and primary cells from patients.

Background: The tumor suppressor protein p53 is frequently mutated in cancer, and cancer cells carrying defects in p53 are generally more resistant to conventional chemotherapy. About 60% of patients with ovarian cancer have p53 mutations. Thus, restoration of wild type function of p53 is a promising strategy for cancer therapy. APR-246 (PRIMA-1MET) belongs to a class of small molecules (quinuclidinones) that reactivate mutated or otherwise non-functional p53 by promoting its correct wt folding thus triggering apoptosis (Lambert et al. Cancer Cell 15, 2009). In various in vitro, ex vivo and in vivo cancer models APR-246 has shown good antitumor activity and a unique pharmacological profile. In a Phase I/II clinical dose-finding study on hematological malignancies and prostate cancer APR-246 had a good safety profile, and both biological and clinical responses were observed (Lehmann et al. J Clin Oncol 30, 2012). A Phase II Proof of Concept study in p53 mutant ovarian cancer patients is currently under way. Here results from combination studies with APR-246 and platinum compounds in p53 mutant ovarian cancer cell lines, and primary cells from patients, are presented. Methods: Cell viability/proliferation was assessed with WST-1, MTT and/or FMCA assay. p53 gene status was determined with Sanger sequencing and single strand conformation analysis. p53 expression was determined with Western immunoblotting. Results: In the ovarian cancer cell line OVCAR-3, with homozygous “hot spot” p53 core domain mutation (R248Q), strong/outstanding synergistic effects with APR-246 and cisplatin were observed (CI Citation Format: Nina Mohell, Jessica Alfredsson, Maria Uustalu, Asa Fransson, Vladimir J.N. Bykov, Klas G. Wiman, Ulf Bjorklund. Strong synergistic effects with cisplatin and APR-246, a novel compound reactivating mutant p53, in ovarian cancer cell lines and primary cells from patients. [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 3448. doi:10.1158/1538-7445.AM2013-3448