Abstract D073: Combination of insulin-like growth factor-1 receptor/insulin receptor (IGF1R/IR) and androgen receptor (AR) antagonists with metformins inhibits triple-negative breast cancer (TNBC) progression in vitro and in vivo

Abstract

Abstract Triple-negative breast cancer (TNBC) affects only about 15% of women with breast cancer (BC) but accounts for almost 50% of all BC deaths. At this time, development of targeted treatments for TNBC is urgently needed. Insulin-like growth factors and diabetes mellitus type 2 are noted to be associated with increased incidence of estrogen receptor-negative BCs such as TNBC particularly among African American patients. Since receptors for insulin-like growth factor-1 receptor/insulin receptor (IGF1R/IR) and androgen receptor (AR) are known to be enriched and to cross-communicate in subtypes of TNBC (Hamilton N et al., Int J Mol Sci 2017;18:2305 [PMCID: PMC5713274]; Hamilton N et al., Biomed Res Int. 2015;2015:925703 [PMCID: PMC4385615]), we first assessed effects of these receptor antagonists on proliferation of human and murine TNBC cells in vitro. Combination treatment with BMS-754807 and/or NVP-AEW541 (IGF1R/IR inhibitors) plus enzalutamide (AR inhibitor) effectively reduced proliferation of human MDA-MB-231, BT549, HCC1937 and murine 4T1 TNBC cells in vitro (P<0.001). Moreover, metformin and analogues of metformin that inhibit TNBC progression in part by interactions with AMPK and with IGFR1/IR pathways elicited further suppression of TNBC cell proliferation when combined with the IGFR1/IR-AR antagonists (P<0.001). Importantly, the combination treatments also reduced the migration in vitro of human and murine TNBC cells to a greater extent than any single agent given alone. Calculations to determine the coefficient of drug interaction (CDI) revealed therapeutic synergy in drug combinations predominantly in those containing BMS-754807. Of note, combination treatments containing BMS-754807 were found to significantly stimulate excess reactive oxygen species (ROS) in vitro, a process that may promote tumor cell apoptosis. In ongoing experiments, novel metformin analogues are also found to inhibit human MDA-MB-231 xenograft progression in vivo (P<0.001). Our findings suggest that combination treatments containing IGF1R/IR and AR antagonists alone and combined with metformins suppress TNBC progression, with potential to impact patient outcome in the future. [Funding by NCI U54 CA1433930; California Breast Cancer Research Program]. Citation Format: Nalo M. Hamilton, PhD, APRN-BC, Diana C. Márquez-Garbán, MD, Michael E. Jung, PhD, Jaydutt Vadgama, Richard J. Pietras, MD, PhD. Combination of insulin-like growth factor-1 receptor/insulin receptor (IGF1R/IR) and androgen receptor (AR) antagonists with metformins inhibits triple-negative breast cancer (TNBC) progression in vitro and in vivo [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D073.