Enhancement of HIF1mediated Tumor Radiosensitization via Vascular Normalization

In this proposal, the combination of vascular normalization with HIF­1 blockade is sug­ gested as a possible means to radiosensitizing tumors. Research has shown that, after ad­ ministering antiangiogenic agents, there is window of vascular normalization in which tumor hypoxia is alleviated, and tumor radiosensitivity is increased. Recent research also shows that HIF­1 blockade after fractionated radiotherapy causes significant tumor vascular radiosen­ sitization. The careful combination of vascular normalization with post­irradiative HIF­1 blockade has the potential to further increase tumor radiosensitivity through the interplay of the effects of both therapies. It is hypothesized that the partial tumor reoxygenation, due to vascular normalization, will restrict the radioprotective effects that HIF­1 inhibition has on distal tumor cells. It is also hypothesized that partial tumor reoxygenation might allow a greater magnitude of HIF­1 activation upon irradiation. This would make the administration of HIF­1 inhibition following the irradiation of a vasculature­normalized tumor a promising method of further radiosensitizing tumors.