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- W2328033342 abstract "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 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 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" @default.
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- W2328033342 date "2013-04-15" @default.
- W2328033342 modified "2023-09-26" @default.
- W2328033342 title "Abstract 1078: The efficacy of the PARP inhibitors olaparib and veliparib for prevention of breast cancer in a mouse model of BRCA1 deficiency." @default.
- W2328033342 doi "https://doi.org/10.1158/1538-7445.am2013-1078" @default.
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