Abstract P4-15-02: The PI3K inhibitor GDC-0032 enhances the efficacy of standard of care therapeutics in PI3K alpha mutant breast cancer models

Abstract

The phosphoinositide 3-kinases (PI3Ks) are lipid kinases that activate the PI3K signaling pathway and play an essential role in regulating breast tumor cell growth, migration, and survival. Activating and transforming mutations in the PIK3CA gene (PI3K alpha) are commonly found in HER2+ breast cancer and ER+ breast cancer. GDC-0032 is a selective, orally bioavailable inhibitor with a Ki of 0.29 nM for PI3K alpha with 30 fold less inhibition of PI3K beta. In addition, GDC-0032 has increased single agent activity against PI3K alpha mutant and HER2 amplified cancer models in vitro and in vivo. The aim of our study was to evaluate the efficacy of GDC-0032 in breast cancer models in combination with standard of care therapeutics including taxanes, endocrine therapies, and HER2 targeted therapies. We evaluated cell viability for a range of dose concentrations of GDC-0032, as single agent and in combinations, in eleven breast cancer cell lines that harbor mutations in PI3K alpha (K111N, E545K, H1047R) and/or over-expressed HER2. GDC-0032 was combined with taxanes (paclitaxel and docetaxel), endocrine therapies (fulvestrant and tamoxifen) or anti-HER2 agents (trastuzumab, pertuzumab or ado-trastuzumab-emtansine) and synergy quantified using the Chou and Talalay method of Combination Index (C.I.). The combination of GDC-0032 with taxanes, endocrine therapies or anti-HER2 therapies were synergistic in the breast cancer cell lines tested based on C.I. values of less than 1.0. The combination of GDC-0032 with docetaxel in vitro resulted in decreased viability as a result of increased cell death. The in vitro results translated in vivo as GDC-0032 enhanced the anti-tumor activity of docetaxel and paclitaxel in MCF7 (E545K) xenografts that resulted in increased tumor regressions when GDC-0032 was dosed daily or intermittently on the same schedule as the taxane. In addition, the combination of GDC-0032 and fulvestrant or tamoxifen resulted in greater efficacy in the MCF7 xenograft model when compared to either agent alone. Enhanced efficacy was also observed when GDC-0032 was combined with trastuzumab or ado-trastuzumab-emtansine in the HER2+ BT474M1 (K111N) xenograft model. Moreover, the triple combinations of GDC-0032/trastuzumab/pertuzumab or GDC-0032/trastuzumab/docetaxel resulted in durable tumor regressions that were sustained in the HER2+ KPL-4 (H1047R) and BT474M1 xenograft models, respectively. All drug combinations with GDC-0032 were well tolerated in vivo based on minimal changes in body weight. Collectively, our preclinical data demonstrate that GDC-0032 enhances the efficacy of standard of care therapeutics in PI3K alpha mutant breast cancer models and provides a strong rationale for further evaluation in patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-02.

Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer

“…The PI3K isoform‐selective inhibitors alpelisib and taselisib have demonstrated promising antitumor activity in preclinical models and clinical studies , summarized below. Both alpelisib and taselisib more potently inhibit p110α than p110β (approximately 250‐fold and 30‐fold greater specificity, respectively) . Taselisib also inhibits PI3K‐δ and PI3K‐γ isoforms .…”

“…Taselisib is another PI3K inhibitor with improved selectivity against mutated versus wild‐type p110α . In PIK3CA ‐mutated breast cancer models, treatment with taselisib plus ET resulted in enhanced antitumor activity compared with single‐agent antiestrogens, including fulvestrant . In a phase II, open‐label, single‐arm study of 60 postmenopausal patients with HR+, HER2− metastatic breast cancer with nonresponse or progression on ≥1 prior ET, taselisib plus fulvestrant demonstrated initial antitumor activity.…”

AKT signaling in ERBB2-amplified breast cancer

“…Similarly, breast cancer cell lines and xenograft models harboring mutations in PIK3CA or amplification of ERBB2 were found to be sensitive to p110β-sparing PI3K inhibitor GDC-0032 in combination with trastuzumab or T-DM1 (Sampath, 2013), and provided the rationale for its ongoing clinical evaluation in combination with anti-ERBB2 therapies.…”

PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting

“…A major obstacle to this approach is the heterogeneity of oncogenic PIK3CA mutations. Some progress has been made with the discovery of GDC0032, which was reported at the 2013 SABCS to have enhanced potency in PIK3CA mutant breast cancer models 180 ; one preclinical study also reported success using stapled peptides to specifically disrupt the interaction of p110α-E545K with IRS1 37 . However, devising strategies to selectively interrupt mutant-specific function remains challenging.…”