Our laboratory is focused on defining the signaling pathways and cytoskeletal mechanisms that control the organization of endothelial cells into new blood vessels within tumors, with the overall goal of identifying strategies for alleviating tumor hypoxia that will consequently improve efficacy of oxygen-dependent radio-therapies. We have identified several signaling pathways and associated effector molecules that are critical for normal capillary morphogenesis and, consequently, attractive targets for "normalizing" tumor blood vessels. These include protein kinase A, the GTPases RhoA, Rac1, and Cdc42, and calpains, all of which contribute to endothelial cell cytoskeletal regulation. Guided by this new basic information, we identified a panel of pre-existing drugs as well as natural products that appropriately alter the cytoskeleton-regulating signaling pathways described above and thereby correct architectural and functional defects associated with pathological tumor blood vessels and, furthermore, reduce tumor hypoxia. Currently, we are testing these pharmacological agents and combinations in pre-clinical cancer models for improvement of radiation therapies.