Abstract 3603: Optimizing combination therapy against antiestrogen-resistance in estrogen receptor positive breast cancer

Abstract

Abstract Approximately 75% of breast cancer incidences are Estrogen Receptor positive (ER+). Treatment of ER+ breast cancer with antiestrogen endocrine therapy targets the proliferative mechanisms of ER using selective ER modulators (SERMs), such as tamoxifen, and selective ER downregulators (SERDs), such as fulvestrant. The resistance to endocrine therapy, either innate or acquired, is clinically diagnosed in up to 50% of patients within 5 years of treatment. Antiestrogen therapy of ER+ mammary cancer cells in vitro and in xenografts does not cause complete cell death or regression. Through the use of combination therapy to target the remaining sub-population of cells, complete regression can be predicted. Our lab has developed endocrine tamoxifen-resistant models through prolonged exposure to tamoxifen, estrogen deprivation, and overexpression of PKCα, a pro-survival pathway component, in addition to a fulvestrant-resistant model through prolonged exposure to fulvestrant. Investigation of the resistance mechanisms will provide insight into potential, combinatorial targets for overcoming endocrine resistance in ER+ breast cancer. Use of spheroidal 3D cell culture provides a physiologically relevant model with sufficient throughput for drug discovery. Establishing spheroids and subsequent treatment predicts the efficacy of combination treatment on tumor regression. Targeting pathways associated with increased prevalence of resistance, such as CDK 4/6, can be employed for clinical therapy. Using both novel in-house and clinical SERMs and SERDs, we have used these multiple cell lines to discover combinatorial targets using both mechanistic and unbiased screening approaches. The use of combination endocrine therapy in tamoxifen-resistant models has shown antiproliferative synergy, and is able to enhance tumor regression in xenografts. By optimizing combinatorial endocrine treatment against both fulvestrant- and tamoxifen-resistance, novel therapeutic approaches are being developed for ER+ breast cancer. Citation Format: Lauren M. Gutgesell, Rui Xiong, Jiong Zhao, Debra A. Tonetti, Gregory R. Thatcher. Optimizing combination therapy against antiestrogen-resistance in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3603. doi:10.1158/1538-7445.AM2017-3603