Abstract 5447: Targeting vascular endothelial growth factor A and tumor hypoxia combined with radiation eradicates sarcomas through destruction of tumor vasculature and thwarting of the hypoxic response

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: In a previous clinical trial, we demonstrated that bevacizumab, an anti-vascular endothelial growth factor A (VEGF-A) antibody, combined with radiation leads to >80% tumor necrosis in about one-half of patients with soft tissue sarcomas. Sarcomas with a poor response to this therapy had upregulation of hypoxia inducible factor 1α (HIF-1α) and HIF-1α target genes. Here, we describe two trimodality approaches to this problem: (1) blockade of HIF-1α using genetic or pharmacologic inhibition and (2) destruction of hypoxic regions of tumors using the hypoxia-activated chemotherapeutic, TH-302. Methods: Trimodality therapies were used in a HT1080 fibrosarcoma xenograft model and the LSL-KrasG12D/+/Trp53fl/fl genetically engineered mouse model of sarcoma. Treated tumors were examined for effects on cancer cells and tumor vasculature. Trimodality therapies were also studied in vitro on four sarcoma cell lines and on two types of endothelial cells. Results: In both mouse models, trimodality therapy with HIF-1α inhibition using low dose doxorubicin or HIF-1α shRNA was significantly better than any bimodality therapy in blocking tumor growth, with tumors growing to only 13-18% size of controls. When hypoxic areas of tumors were targeted with TH-302, this alternative trimodality therapy was again better than any bimodality therapy in blocking sarcoma tumor growth (tumor size 9% of controls), and tumors failed to grow after stopping treatment for more than 2 months. Analysis of treated tumors demonstrated the predominant effect with both trimodality therapies was through induction of endothelial cell apoptosis (2.6-3.3 fold more than the best bimodality therapy) and destruction of tumor vasculature (86-89% less microvessel density than controls). When the effects of trimodality therapy were examined in vitro, decreases in proliferation and colony formation and induction of apoptosis from trimodality therapy were much more pronounced in tumor-derived endothelial cells than in sarcoma cell lines. Conclusion: HIF-1α inhibition or hypoxia-activated chemotherapy is effective when combined VEGF-A inhibition and radiation in controlling sarcomas by maximizing destruction of tumor vasculature and blocking the hypoxic response. Clinical trials are currently in development using both these trimodality strategies. Citation Format: Changhwan Yoon, Hae-June Lee, Do Joong Park, William D. Tap, T. S. Karin Eisinger-Mathason, David G. Kirsch, M. Celeste Simon, Sam S. Yoon. Targeting vascular endothelial growth factor A and tumor hypoxia combined with radiation eradicates sarcomas through destruction of tumor vasculature and thwarting of the hypoxic response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5447. doi:10.1158/1538-7445.AM2014-5447