Abstract LB-166: PARP inhibition effects on endocrine therapy and resistance in estrogen receptor positive (ER+) breast cancer models
Authors: Nardone Agostina , Goldstein Amit , Shea Martin J. , Mithchell Tamika , Fu Xiaoyong , De Angelis Carmine , Hu Huizhong , Xu Xiaowei , Rajendran Mahitha , O'Connor Mark , Locker Gershon , Hilsenbeck Susan , Osborne Kent , Schiff Rachel 
Published: August 2015

Abstract
Background: Poly [ADP-ribose] polymerase (PARP) is an important mediator of DNA damage repair. Preclinical and clinical studies have indicated PARP inhibitors (i) as promising agents in DNA-repair-defective cancers, especially in the presence of BRCA1/2 alterations. Recent evidence also suggests a role for additional DNA damage-independent functions of PARP, involving transcriptional and epigenetic regulation. Particularly, PARP-1 can interact with the estrogen receptor (ER) and modulate its transcriptional activity in vascular smooth muscle cells, and PARPi can circumvent endocrine resistance in prostate cancer cells. However, the effect of PARPi on the efficacy of endocrine therapy (EndoTx) in ER+ breast cancer is unknown. Here we aimed to establish these effects using the PARPi olaparib (AZD2281, Olap) in our preclinical models.
Methods: The effects of Olap (0.01-1μM) alone or in combination with EndoTx [estrogen deprivation (ED) or tamoxifen (Tam)] were tested in vitro in three ER+ parental cell lines (MCF7, ZR75-1, and T47D; BRCAwt) and their endocrine resistant (R) derivatives. Clonogenic assays were used to assess Olap-induced changes in cell growth. In vivo, ovariectomized nude mice bearing 200 mm3 tumors growing in the presence of estrogen supplementation (E2 pellets), were randomized to either continued E2 (control), ED, or ED+Tam; all ± oral Olap (100mg/kg daily).
Results: In MCF7 parental cells in vitro, Olap, in a dose dependent manner, inhibited E2-stimulated growth and increased the growth inhibitory effect of EndoTx. In addition, at a clinically relevant dose (1μM), Olap significantly inhibited the growth of MCF7 EndoR cell derivatives. Similar results were also observed in the other 2 ER+ cell models. In vivo, long-term Olap-treatment in the presence of EndoTx (Tam ∼200days, and ED ∼300days) was well tolerated and no apparent drug-related toxicity was observed. Olap did not affect the growth of E2-stimulated MCF7 xenografts. In contrast, Olap enhanced sensitivity to Tam by delaying time to tumor progression (TTP; size doubling) from a median of 95 days to 155 days (p = 0.03), and numerically but not significantly reduced time to tumor regression (TTR; size halving) from 138 to 51 days (p = 0.2). Olap also numerically accelerated median time to tumor regression in the presence of ED (34 ED vs. 25 days ED+Olap; p = 0.23), but had no effect on TTP (P = 0.36).
Conclusion: Our results suggest a potential role for Olap in enhancing EndoTx efficacy and circumventing resistance in the absence of BRCA mutations. The absence of any toxicity and negative interaction by adding Olap to EndoTx in the in vivo experiment supports the inclusion of ER+ breast cancer patients in clinical trials using PARPi. Further studies are warranted to better understand the biology of PARP and the efficacy of PARPi in ER+ breast cancer, especially in the presence of EndoTx and resistance.
Citation Format: Agostina Nardone, Amit Goldstein, Martin J. Shea, Tamika Mithchell, Xiaoyong Fu, Carmine De Angelis, Huizhong Hu, Xiaowei Xu, Mahitha Rajendran, Mark O'Connor, Gershon Locker, Susan Hilsenbeck, Kent Osborne, Rachel Schiff. PARP inhibition effects on endocrine therapy and resistance in estrogen receptor positive (ER+) breast cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-166. doi:10.1158/1538-7445.AM2015-LB-166