The Role of Tumor-Vessel Interface in Multimodal Cancer Therapy

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Tumors protect their vasculature from radiation- and chemotherapy induced damage by releasing pro-angiogenic and pro-survival factors. Thus tumor-vessel communication is emerging as an important target to circumvent chemo- and radio-resistance. Very recently, molecular, cellular and physiological rationales for the beneficial use of trimodal cancer therapy consisting of antiangiogenesis, radiotherapy and chemotherapy were provided by our laboratory. Antiangiogenic treatment enhances the effects of radiotherapy and chemotherapy by resensitizing endothelial cells to apoptosis and normalizing the tumor vasculature. Here we propose a four step process to optimize the concept of trimodal therapy: first, we plan to systematically characterize the molecular and pathophysiological events that are involved in ¿tumor-vessel-interaction¿ in response to multimodal therapies with emphasis on the emerging problem of resistance development to adjuvant antiangiogenic treatment. After confirming the key genetic players of systems biology identified by global expression profiling the promising ¿targets¿ will be functionally evaluated for their ability to modulate chemo-radiotherapy response. In this context we also aim to investigate the yet unknown role of radiotherapy-induced downregulation of endogenous angiogenesis inhibitors, endostatin and thrombospondin, in acquired tumor radio-resistance. Finally, we will use these data to rationally design meaningful ¿antiangiogenic cocktails¿ and to test for their optimal therapeutic scheduling.