Antiangiogenic activity of the HSP90 inhibitor ganetespib in pancreatic cancer models

Abstract

Heat shock protein 90 (HSP90) has a central role in the regulation of transcriptional factors that modulate angiogenesis and growth. Ganetespib (G) is a functional inhibitor of HSP90 being studied in a broad range of clinical trials. We tested the hypothesis that functional inhibition of HSP90 by G can inhibit angiogenesis and growth in vitro and in vivo models of pancreatic cancer. PANC‐1, and HPAC cell lines were treated with vehicle or G (50nM) for 24 h and lysates were analyzed by Western blot. Egg CAM and matrigel plug assays were performed to quantify the effects of G on angiogenesis. Efficacy of G (100mg/kg) was assessed in mice bearing HPAC and ASPC‐1 xenograft. Western blot analyses demonstrated a significant reduction in intracellular HIF‐1á and VEGF protein levels in PANC‐1 and HPAC cells treated with G. Results from ELISA assays showed that G reduced VEGF secretion in the culture medium from both pancreatic lines. G treatment reduced angiogenesis compared to vehicle in all three models. Animals with human pancreatic tumor xenografts treated with G had significant tumor growth delay and inhibition of angiogenesis. The preclinical data demonstrates that G can inhibit pancreatic cancer growth and angiogenesis, suggesting that targeting HSP90 is a rational new approach to pancreatic cancer therapy to be explored in clinical trials.