Abstract PD5-3: Anti-metastatic activity, chemotherapeutic enhancement and therapeutic potential of targeting Hsp90 with ganetespib in triple negative breast cancer

Abstract

Background: While the incidence of triple negative breast cancer (TNBC) is only 10-20%, these tumors show a disproportionate mortality for breast cancer patients. Due to a lack of effective molecular targets in this disease, therapeutic options are largely limited to systemic chemotherapeutic approaches which have shown disappointing efficacy in the metastatic setting. Here we undertook a comprehensive evaluation of the activity of the drug candidate, ganetespib, a potent inhibitor of heat shock protein 90 (Hsp90), in this malignancy. Methods: The sensitivity of TNBC cells to ganetespib was determined in viability assays using a panel of tumor lines. The effects of ganetespib exposure on client proteins and their effector pathways were examined by Western blot and reverse phase protein array analysis. The anti-metastatic activity of ganetespib was evaluated using a 4T1 metastasis model. Combinatorial drug analyses were performed with chemotherapeutic agents. DNA damage and cell cycle disruption were assessed using the comet assay, Western blotting and fluorescence microscopy. The in vivo efficacy of the compound, both as a single agent and in combination, was established using MDA-MB-231 xenograft models. Computed tomography scans were obtained for a metastatic TNBC patient undergoing ganetespib treatment. Results: Ganetespib reduced cell viability in TNBC cell lines with low nanomolar potency. Ganetespib treatment induced robust destabilization of multiple client proteins and oncogenic signaling pathways and suppressed lung metastasis in the experimental model. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin + cyclophosphamide (AC) regimen in MDA-MB-231 xenograft models. 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 lesions was seen in the patient while on ganetespib monotherapy. Conclusion: The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC. In particular, the capacity of ganetespib to potentiate the activity of standard of care chemotherapeutics provides a rationale for the exploration of this agent in novel combinatorial treatment strategies for this disease. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-3.