Abstract 1078: The efficacy of the PARP inhibitors olaparib and veliparib for prevention of breast cancer in a mouse model of BRCA1 deficiency.
Authors: Liby Karen T. 
Published: August 2014

Women with inherited mutations in a BRCA gene have a 65-85% lifetime risk of developing breast cancer. Currently, “watchful waiting” or bilateral prophylactic mastectomy is offered to these high risk women, although they are ideal candidates for effective chemoprevention. Because BRCA proteins play crucial roles in homologous recombination, inhibiting base excision repair, the default pathway in BRCA-deficient cells, induces cell death in these cells but not in normal cells. PARP (poly ADP ribose polymerase) inhibitors block base excision repair, and PARP inhibitors such as olaparib and veliparib are being evaluated in clinical trials. However, these drugs have not been tested for their ability to prevent cancer. When conditional knockout (co) of BRCA1 is coupled with a mutation in p53, Brca1Co/Co;MMTV-Cre;p53+/− mice develop ER- mammary tumors by 6-10 months of age. In a pilot feeding study, female mice were fed olaparib (200 mg/kg diet) or veliparib (100 mg/kg diet) for 2 wks, and tissue levels averaged 40 nM and 100 nM in plasma and 20 nM and 100 nM in the mammary glands, respectively. When started in diet at 10 wks of age and fed continuously, both drugs significantly (P &lt; 0.005) delayed tumor development by 2.4-6.6 wks. Despite the higher tissue levels of veliparib in the mice, olaparib was more effective than veliparib. Mammary tumors were detected at an average of 28.4 ± 0.9 wks of age in the control group vs. 34.9 ± 1.1 wks in mice fed olaparib; mammary tumors were detected at an average age of 30.0 ± 0.6 wks in mice fed veliparib vs. 27.5 ± 0.5 wks in the control group (n &gt; 14 mice/group). Although both drugs were well-tolerated at these doses, the lowest effective dose of a drug should be used for prevention. In a dose de-escalation study, mice were fed olaparib at 50-100 mg/kg diet. Both doses significantly (P &lt; 0.05) delayed tumor development by 3.3-3.5 wks compared to the controls. An intermittent prevention strategy was also used. This approach is clinically significant because the introduction of rest periods between doses should minimize drug resistance or any unforeseen toxicities from PARP inhibitors that may appear upon prolonged drug exposure. In this strategy, mice were fed olaparib (200 mg/kg diet) for 2 wks at a time, followed by 4 wk rest periods of control diet. Intermittent treatment with olaparib is nearly as effective as continuous feeding and increases the age of tumor onset to 34.7 ± 0.9 wks vs. 29.7 ± 1.0 wks in the control group (P &lt; 0.001; n &gt; 16 mice/group). Ongoing studies are testing whether olaparib induces apoptosis in the mammary glands and tumors of these mice. In summary, these studies demonstrate that the PARP inhibitors olaparib and veliparib are effective for delaying tumor development in BRCA1-deficient mice. Moreover, dose de-escalation and intermittent treatment are important new strategies that need to be developed for chemoprevention. Supported by Susan G. Komen for the Cure

Citation Format: Karen T. Liby. The efficacy of the PARP inhibitors olaparib and veliparib for prevention of breast cancer in a mouse model of BRCA1 deficiency. [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 1078. doi:10.1158/1538-7445.AM2013-1078