Preclinical Activity Profile and Therapeutic Efficacy of the HSP90 Inhibitor Ganetespib in Triple-Negative Breast Cancer

David A Proia,Geoffrey I Shapiro,Iman El-Hariry,Masazumi Nagai,Chaohua Zhang,Richard C Bates,Jaime Acquaviva,Donald L Smith,Suqin He,Jim Sang,Manuel Sequeira,Neil Spector,Sara Tolaney,John-Paul Jimenez

doi:10.1158/1078-0432.ccr-13-2166

Abstract

Treatment options for patients with triple-negative breast cancer (TNBC) are largely limited to systemic chemotherapies, which have shown disappointing efficacy in the metastatic setting. Here, we undertook a comprehensive evaluation of the activity of ganetespib, a potent inhibitor of HSP90, in this malignancy. The antitumor and antimetastatic activity of ganetespib was investigated using TNBC cell lines and xenograft models. Combinatorial drug analyses were performed with chemotherapeutic agents and concomitant effects on DNA damage and cell-cycle disruption were assessed in vitro; antitumor efficacy was assessed in vivo. Metabolic and objective tumor responses were evaluated in patients with metastatic TNBC undergoing ganetespib treatment. Ganetespib simultaneously deactivated multiple oncogenic pathways to potently reduce cell viability in TNBC cell lines, and suppressed lung metastases in experimental models. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin-cyclophosphamide regimen in TNBC xenografts. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung and lymphatic lesions were seen in patients on ganetespib monotherapy. The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC.

Highlights

Breast cancer remains the leading cause of cancer-related mortality in women worldwide [1]
We show that the triple-negative breast cancers (TNBC) phenotype is highly sensitive to the pleiotropic effects of HSP90 inhibition conferred by ganetespib exposure
In BT-20 cells, ganetespib treatment resulted in a dose-dependent destabilization of EGFR, IGF-IR, MET, and CRAF (Fig. 1B) accompanied by inactivation of downstream effectors and mammalian target of rapamycin signaling (4E-BP1, ribosomal protein S6)

Summary

Introduction

Breast cancer remains the leading cause of cancer-related mortality in women worldwide [1]. Despite a remarkable degree of heterogeneity, human breast tumors have been classified into at least five "intrinsic" subtypes on the basis of discrete molecular signatures identified through gene expression profiling [2,3,4,5] These include normal breastlike, the hormone receptor-positive (estrogen and progesterone receptors; ER and PR) luminal A and luminal B subtypes, human EGF receptor 2 (HER2)-positive, and basal-like. In contrast with effective tailored treatments for luminal or HER2-amplified tumors, the absence of defined molecular targets in TNBC has restricted therapeutic options to systemic chemotherapies in the adjuvant or metastatic setting [6] These cancers remain high risk with unfavorable prognoses [7, 12]

Methods

Results

Conclusion