Abstract 12: Localized delivery of the PARP inhibitor Talazoparib for chemoprevention of breast cancer

Abstract

Abstract Mutations in BRCA genes are the leading cause of hereditary breast cancer and dramatically increase the lifetime risk of developing breast cancer. Anti-estrogen drugs are approved to reduce the risk of developing invasive breast cancer, but they are not effective for women with germline BRCA mutations and are limited by undesirable toxicities. Radical mastectomy provides a surgical option for high-risk patients for cancer prevention, but the physical and emotional challenges of such a radical surgery confirm that alternative approaches are needed. Our goal is to develop novel chemopreventive agents that are effective and safe for BRCA carriers. PARP inhibitors are effective for treating BRCA-mutated breast cancer patients, and we have shown that these drugs significantly delayed tumor development in BRCA-deficient mice. Here, we developed a novel implantable formulation of the PARP inhibitor Talazoparib for local delivery and thus provide a new therapeutic strategy for prevention of breast cancer. Talazoparib (TLZ) was encapsulated into spacer implants (InCeT-TLZ, 25 μg/mm) and is released in a linear manner from the implant over 30 days. When BRCA-deficient breast cancer cells were treated with the InCeT-TLZ implant in vitro, 83.1%±1.4% of the cells were dead after 7 days of treatment. To determine in vivo efficacy, age-matched BRCACo/Co;MMTV-Cre;p53+/-mice were randomized into three groups: empty spacers (2 mm), oral TLZ (50 μg given over 4 weeks), and InCeT-TLZ (50 μg, 2 mm). Using brachytherapy needles, spacers were implanted into mammary glands of the BRCA-deficient mice at 12, 16 and 20 weeks of age, before tumors had developed, and tissues were harvested 4 weeks after implantation. InCeT-TLZ significantly (p<0.05) increased DNA damage by 6.9 fold and decreased proliferation by 51.9% in the mammary gland, determined by γH2AX and PCNA staining, respectively, compared to empty spacer control. Notably, the number of mice (N=33-35/group) that developed hyperplasia in the mammary glands were significantly (p<0.05) lower with InCeT-TLZ spacers (22.9%) compared to the empty spacer group (63.6%) or oral TLZ (57.6%). Moreover, significantly (p<0.05) lower red blood cell counts were observed after oral TLZ treatment but not with InCeT-TLZ. Oral TLZ treatment also induced a significantly lower number of white blood cells (9.6±0.4 K cells/μl) compared to InCeT-TLZ group (11.4±0.6 K cells/μl). This study provides proof of concept for a novel and safe chemopreventive strategy using localized delivery of a PARP inhibitor for high risk individuals. Additional studies will be done to directly evaluate the effects of InCeT-TLZ for preventing tumor development. Work supported by Breast Cancer Research Foundation and HHSN261201800026C. Citation Format: Di Zhang, Bijay Singh, Jessica Moerland, Owen Mitchell, Lizbeth Lockwood, Sarah Carapellucci, Srinivas Sridhar, Karen Liby. Localized delivery of the PARP inhibitor Talazoparib for chemoprevention of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 12.