Preclinical activity profile and therapeutic efficacy of the Hsp90 inhibitor ganetespib in triple-negative breast cancer
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale du ganetespib, un inhibiteur de la protéine de choc thermique Hsp90, pour le traitement d'un cancer du sein triplement négatif
Purpose: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 heat shock protein 90 (Hsp90), in this malignancy. Experimental Design:The antitumor and anti-metastatic 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 metastatic TNBC patients undergoing ganetespib treatment. Results: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. Conclusions: The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC.