Abstract P5-19-02: Selective PI3K and dual PI3K/mTOR inhibitors enhance the efficacy of endocrine therapies in breast cancer models

Abstract

Purpose: Phosphoinositide 3-kinases (PI3K) are lipid kinases that can regulate breast tumor cell growth, migration and survival. Standard of care drugs such as estrogen receptor (ER) antagonists including fulvestrant and tamoxifen, and aromatase inhibitors such as letrozole are indicated for the treatment of hormone receptor positive breast cancer. The current study is focused on investigating preclinical activity in breast cancer models, for GDC-0941, a class I PI3K inhibitor, GDC-0032, a PI3K inhibitor, and GDC-0980, a dual mTOR kinase and class I PI3K inhibitor. Investigation into PI3K inhibitor efficacy in combination with endocrine therapies is also explored. Experimental Design: A panel of ER+ breast cancer cell lines were treated with GDC-0941, GDC-0032 and GDC-0980 either as single agents or in combination with fulvestrant or tamoxifen and assayed for cellular effects. MCF-7 cells ectopically expressing aromatase were utilized to test the efficacy of aromatase inhibitors in combination with PI3K inhibitors in vitro. In addition, human xenografts of breast cancer cell lines were employed to assess combination efficacy of PI3K inhibitors with fulvestrant and tamoxifen in vivo. Results: Combination of GDC-0941, GDC-0032 or GDC-0980 with endocrine therapies resulted in a decrease in cellular viability and an increase in cell death. Synergy of PI3K inhibitor combinations with fulvestrant or tamoxifen was assessed using Combination Index (C.I.), and C.I. values as low as 0.1 indicated strong synergy in some contexts. Combination activity of PI3K inhibitors and letrozole was also observed in MCF7 cells expressing aromatase. In MCF-7 xenografts, the combination of GDC-0980, GDC-0032 and GDC-0941 enhanced activity of fulvestrant resulting in tumor regressions and tumor growth delay (116% tumor growth inhibition (TGI) for GDC-0980 and 91% TGI for GDC-0941 and GDC-0032). In addition, the combination of GDC-0941 or GDC-0032 with tamoxifen enhanced the efficacy of tamoxifen in vivo (83%TGI for GDC-0941 and 102%TGI for GDC-0032). Mechanism of action and biomarker studies are underway. Conclusion: Collectively, the non-clinical efficacy data provide a strong rationale to evaluate the combination of PI3K inhibitors with anti-estrogen therapy in hormone receptor positive breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-19-02.

The Therapeutic Potential of PI3K/Akt/mTOR Inhibitors in Breast Cancer: Rational and Progress

“…The PI3K/mTOR inhibitors, NVP-BEZ235 and GDC0980, are also under evaluation. In preclinical studies, fulvestrant combined with GDC0980, GDC0032, and GDC0941 inhibited tumor growth in MCF-7 xenografts [Friedman et al, 2012]. A combination of everolimus with tamoxifen, and LY294002 increased the antitumor effects over tamoxifen alone or tamoxifen with everolimus in a BC cell line [Chen et al, 2013].…”

Consequences of the Convergence of Multiple Alternate Pathways on the Estrogen Receptor in the Treatment of Metastatic Breast Cancer

“…In preclinical studies, GDC0980, GDC0032, and GDC0941, given in combination, enhanced activity of fulvestrant in MCF-7 xenografts, resulting in tumor regression and tumor growth delay. 84 A combination of tamoxifen, everolimus, and LY294002 produced increased antitumor effects compared with tamoxifen alone or tamoxifen and everolimus in a breast cancer cell line. 85 In addition, treating breast cancer cells with BEZ235 induced apoptosis when combined with estrogen deprivation, suggesting potential activity in HR þ breast cancer.…”