Abstract 1373: Targeting angiogenesis and tumor growth with the Hsp90 inhibitor NVP-AUY922 in a model of pancreatic cancer: impact on cMet, VEGFR2 and PDGFR signaling

Heat shock protein 90 (Hsp90) has been identified as a critical regulator of oncogenic protein stability. Therefore, Hsp90 has emerged in recent years as a promising new target for anticancer therapies. In previous studies, we were able to demonstrate, that pancreatic cancer harbors multiple such targets, which can effectively be inhibited by geldanamycin derivates, leading to significant growth inhibition. Here, we follow-up on this aspect by investigating effects of a novel resorcinylic isoxazole amide Hsp90 inhibitor (NVP-AUY922) in human pancreatic cancer. Human pancreatic cancer cells (L3.6pl, HPAF-II, BxPC3, MiaPaCa2), vascular smooth muscle cells (VSMC) and endothelial cells (HMVEC) were employed. Cytotoxic effects were assessed by MTT analyses. Effects of Hsp90 blockade on signaling pathways were investigated by Western blotting. The impact of NVP-AUY922 on cell migration was evaluated in modified Boyden chambers. Effects of NVP-AUY922 on tumor growth and vascularization were investigated in subcutaneous xenograft models. Mice received either NVP-AUY922 (50 mg/kg/w, or 25 mg/kg 3x/week), or vehicle by intraperitoneal injections. The Hsp90 inhibitor dose-dependently reduced the proliferation of pancreatic cancer cells in vitro and Western blotting showed that NVP-AUY922 effectively blocks STAT3, Akt, Erk, and FAK activation in cancer cells. In addition, NVP-AUY922 treatment resulted in a down-regulation of cMet and IGF-IR and a marked inhibition of tumor cell migration in vitro. Interestingly, in endothelial cells (HMVEC), NVP-AUY922 not only significantly reduced cell survival/proliferation in MTT analyses, but also markedly decreased VEGF-R2 activation, as well as Akt, STAT3, and Erk phosphorylation. NVP-AUY922 also significantly reduced VEGF-A-mediated EC migration in vitro, suggesting a potential antiangiogenic effect of this compound. Similarly, in VSMCs, cell proliferation was significantly diminished while activation of PDGF-Rβ and phosphorylation of Erk and Akt were substantially inhibited. The PDGF-BB-mediated migration of VSMCs was significantly abrogated. In vivo, treatment with NVP-AUY922 significantly reduced tumor growth rates of pancreatic cancer cells. Immunhistochemical analyses of tumor tissues showed that blocking Hsp90 with NVP-AUY922 significantly reduces vascularization. In conclusion, NVP-AUY922 is a novel potent inhibitor of Hsp90 that effectively disrupts multiple oncogenic signaling cascades in pancreatic cancer cells, and significantly reduces tumor growth in vivo. Moreover, direct effects of NVP-AUY922 on endothelial cells and vascular smooth muscle cells suggest that NVP-AUY922 could be used for both antineoplastic and antiangiogenic therapy of pancreatic cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1373.