Abstract 2965: Olaparib and veliparib as effective PARP inhibitors for cancer prevention in a BRCA1-deficient mouse model

Abstract An inherited mutation in the BRCA1 gene leads to genomic instability and those with this mutation have a 50-80% risk for developing breast cancer by age 70. Though bilateral prophylactic mastectomy and surveillance are viable options for this high-risk population, chemoprevention may serve as a good alternative strategy. BRCA1 functions to repair double stranded DNA breaks via homologous recombination and as such, BRCA1 mutations force the cells to rely on other DNA repair mechanisms such as base excision repair, a process which requires Poly ADP ribose polymerase (PARP). Thus, PARP inhibition in BRCA1-deficient cells may induce apoptosis in these cells, which would otherwise develop into a tumor, while leaving normal cells intact. Olaparib and veliparib are promising PARP inhibitors that are currently in clinical trials for breast cancer treatment; however, their role in cancer prevention has not been examined. Hence, this study evaluated the effect of these PARP inhibitors in chemoprevention in the BrcaCo/Co;MMTV-Cre;p53+/- mouse model. Mice were fed continuously with olaparib (200 mg/kg diet) or veliparib (100 mg/kg diet) and tumor development was assessed. Both olaparib and veliparib significantly delayed tumor development by 6.5 and 2.4 weeks respectively (p<0.05) compared to their controls but olaparib was more effective than veliparib. To determine the lowest dose required for prevention, a dose de-escalation study was done and tumor development was assessed in mice fed with 100, 50, or 25 mg/kg of olaparib in diet. Tumor development was significantly delayed by 3.2 and 3.5 weeks (p<0.05) in mice fed with 50 and 100 mg/kg of olaparib diets respectively compared to their controls. To circumvent the possibility of drug resistance and adverse drug reaction from prolonged use of olaparib, an intermittent dosing regimen was examined where mice cycled through 200 mg/kg of olaparib diet for 2 weeks followed by a 4-week rest period of control diet. Intermittent treatment with olaparib significantly delayed tumor development by 5.7 weeks (p<0.05), which was almost as effective as continuous olaparib treatment. BrdU staining revealed that olaparib significantly reduced proliferation (p<0.05) when compared to their controls at both 24 (9.9% vs. 13.5% in hyperplastic areas; 4.5% vs. 9.5% in mammary ducts) and 30 weeks (9% vs. 15.9% in hyperplastic areas; 8.9% vs. 17.6% in mammary ducts) of age. A significant increase in apoptosis in hyperplastic areas from mice treated with olaparib compared to the control group (12.3% vs. 8.4%; p<0.05) was also observed by TUNEL staining at 30 weeks. Taken together, these studies demonstrated that olaparib is an effective agent that can be used intermittently to delay tumor development by reducing proliferation and inducing apoptosis in BRCA1-deficient mice. These results highlight the potential for using PARP inhibitors as novel preventive strategies to manage cancer risk in BRCA1 mutation carriers. Citation Format: Ciric To, Charlotte R. Williams, Darlene B. Royce, Ryan M. Collins, Michael B. Sporn, Karen T. Liby. Olaparib and veliparib as effective PARP inhibitors for cancer prevention in a BRCA1-deficient mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2965. doi:10.1158/1538-7445.AM2014-2965