Abstract AP21: A NOVEL TARGET FOR OVERCOMING ADAPTIVE RESISTANCE TO ANTI-ANGIOGENIC THERAPY IN OVARIAN CANCER

Abstract

Abstract Anti-angiogenic therapy such as anti-VEGF antibody (AVA) has been being increasingly applied in patients with ovarian cancer, while vast majority developed adaptive resistance, highlighting the need for new therapies. We have screened a cohort of patients with high-grade serous cancer (HGSC) using cDNA-genomic array and immunohistochemistry. Our results indicated that p130cas [Crk-associated substrate], a central node in FAK/Src-mediated angiogenesis, was significantly upregulated in tumor-associated vascular endothelium, and the clinical analysis showed that HGSC patients with increased vascular p130cas have significantly shorter disease-progression survival than those with lower vascular p130cas levels. Our cell-based studies showed that AVA treatment in endothelial cells led to internalization of a 100-kD fragment of VEGFR2, which was released by caspase-10 cleavage from membrane-tethered VGFR2. This 100-kD form of VEGFR2 bound with TNKS1BP1 (a tankyrase-1-binding protein involved in p53-mediated cell cycle arrest) and internalized into LC3-tagged autophagosomes or translocated into nucleus to initiate cell death. Furthermore, the gene ablation of p130cas with CRISPR/CAS9 in endothelial cells that were originally resistant to AVA therapy re-sensitized them to AVA treatment. Our in vivo studies on targeting vascular p130cas with host-specific siRNA showed a robust inhibition of tumor growth and progression in orthotopic HGSC tumors through initiating autophagy-associated cell death in tumor-associated endothelial cells. To functionally characterize role of vascular p130cas in angiogenesis, we established the p130casflox/flox-Tie2Cre genomic-engineered mice (GEM) model. Using the ID8 syngeneic model, we found that depletion of vascular p130cas diminished resistance to AVA therapy and compromised angiogenesis by inducing elevated VEGFR2/TNKS1BP1 in autophagosomes and nucleus of tumor-associated endothelial cells, which were followed by cell death. To further explore the therapeutic potential of blocking tumor-associated vascular p130cas as a novel anti-angiogenic strategy, we have constituted a cell-permeable, peptide-nanoparticle complex using a p130cas antagonist encapsulated with biodegradable, long-circulating, core-crosslinked polymeric micelles (CCPM). This CCPM-p130cas antagonist contains a mutated Src-binding domain and is linked with Arg-Gly-Asp (RGD) peptide, which specifically targets angiogenic endothelial cells. We also performed the cell-based studies to show that this CCPM-p130cas antagonist is able to bind to the FAK and Src complex with high affinity and effectively block FAK/Src mediated angiogenic property in endothelial cells. Ongoing studies are focused on investigating the therapeutic efficacy and mechanism of actions for RGD-CCPM-p130cas antagonist as a novel anti-angiogenic therapy to overcome adaptive resistance occurred in patients with HGSC. In summary, our studies provided new knowledge regarding the pivotal role of vascular p130cas in tumor-associated endothelial vasculature, and the critical pre-clinical evidences for applying the RGD-CCPM-p130cas antagonist as a novel therapeutic for treatment of ovarian cancer. Citation Format: Yunfei Wen, Alpa M Nick, G Lopez-Berestein, Gary E Gallick, Robert L Coleman Robert , Mien-Chie Hung, and Anil K Sood. A NOVEL TARGET FOR OVERCOMING ADAPTIVE RESISTANCE TO ANTI-ANGIOGENIC THERAPY IN OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP21.