Abstract 2326: Antiangiogenic effects associated with the inhibition of HSP90 in colorectal cancer

Abstract

Abstract Purpose/Objectives: Angiogenesis has a central role in tumor growth and metastasis. Inhibition of angiogenesis has been shown to improve outcomes of patients with advanced stage colorectal cancer receiving standard chemotherapy regimens. HSP90 has a central role in the regulation of transcription factors that modulate the expression of angiogenic cytokines. Ganetespib is a small molecule functional inhibitor of HSP90. We tested the hypothesis that HSP90 inhibition by ganetespib can inhibit angiogenesis in colorectal cell lines. Methods: Two colorectal cancer (CRC) cell lines were used, HCT-116 and HT-29. Cells were either untreated (control) or treated with ganetespib at 50 nM for 24 hours. Western blot and RT-PCR analyses were carried out to determine the effect of ganetespib on HIF-1alpha and vascular endothelial growth factor (VEGF) expression. ELISA for VEGF expression was performed on the medium of CRC cells to evaluate the effects of ganetespib on VEGF secretion. Tube formation assays and chicken egg chorioallantoic membrane (Egg CAM) assay were also performed. Results: Western blot analyses demonstrated significant (p<0.001) inhibition of HIF-1alpha and VEGF expression in both cell lines treated with ganetespib. RT-PCR demonstrated significant (p<0.0001) downregulation of VEGF transcription. Similarly, ELISA assay demonstrated significant inhibition of VEGF expression in the culture medium in both CRC cell lines. The HUVEC tube formation and the egg CAM assays further confirmed that treatment of the cell lines with ganetespib inhibited angiogenesis. Conclusions: HSP90 inhibition has significant antiangiogenic effects in preclinical models. Evaluating HSP90 inhibitors in conjugation with chemotherapy in colorectal cancer is a rational approach that could have a significant impact on the outcome of this deadly and common disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2326. doi:1538-7445.AM2012-2326