Abstract TMEM-041: OVERCOMING ACQUIRED RESISTANCE TO ANTI–ANGIOGENESIS THERAPY BY TARGETING VASCULAR P130CAS

Angiogenesis is an essential function in tumor growth and metastasis, which is also a dynamic process systematically regulated by a number of factors. The vascular endothelial growth factor (VEGF)–mediated pathway is the most widely studied signaling complex involved in angiogenesis in ovarian cancers, and has been proven to play a critical role in tumor angiogenesis by serving as a potent mitogen2,3. Bevacizumab (Bev), a FDA proved reagent for many cancers including ovarian cancer, is a humanized monoclonal IgG1 antibody directed against human VEGF and induces endoplasmic reticulum stress-dependent apoptosis4-6. However, the efficacy of Bev treatment is modest, and >80% ovarian cancer patients eventually develop acquired resistance, which highlights the need for new targeting therapies. Our whole-genomic screening data indicated that p130cas [Crk-associated substrate (Cas)] was significantly upregulated in ovarian tumor endothelial cells compared with normal counterparts. We previously reported that silencing p130cas in epithelial ovarian cancer cells induced autophagic cell death7, a type II programmed cell death. In this project, we propose to evaluate the therapeutic potential of blocking p130cas in tumor-associated endothelial vasculature as a novel anti-angiogenic strategy. On the basis of our preliminary data, we hypothesize that targeting p130cas in angiogenic endothelium will disrupt the coupling between VGEFR2 and αυβ3/5integrin, block FAK/Src-mediated angiogenesis, enhance the fusion of VEGFR2-containing endosomes with late-stage autophagosomes, and initiate Beclin-1–dependent autophagic cell death that is independent of apoptosis, which eventually leads to inhibition of angiogenesis and tumor progression. Using an array of histopathologic, molecular and cellular approaches, we have gained the following clinical and functional data: 1) high levels of p130cas in endothelial cells inversely correlated with levels of VEGFR-2 and was required for developing acquired resistance to anti-VEGF antibody (AVA) therapy; 2) p130cas was highly expressed in the endothelial vasculature in patients with high-grade serous ovarian cancer (HGSC) and correlated with shorter disease-free survival; 3) targeting vascular p130cas with host-specific siRNA robustly inhibited growth of xenograft HGSC tumors in vivo; and 4) blockade of p130cas inhibited proliferation of endothelial cells with acquired resistance to AVA therapy by initiating a novel cell death mechanism associated with autophagy. Given that this type of cell death mechanism is independent of the apoptotic machinery8-11, we expect that targeting vascular p130cas in HGSC models will serve as a novel anti-angiogenic approach by providing an alternative pathway to overcome apoptotic resistance during acquired resistance to anti-VEGF antibody therapy4-6. Citation Format: Yunfei Wen, PhD. OVERCOMING ACQUIRED RESISTANCE TO ANTI–ANGIOGENESIS THERAPY BY TARGETING VASCULAR P130CAS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-041.