Abstract A42: Antiangiogenic-induced increase in tumor hypoxia in RCC and NSCLC human tumor xenografts and its selective targeting by the hypoxia-activated prodrug TH-302: A model for clinical exploration?

Several published studies have demonstrated an increase in tumor hypoxia after administration of anti-angiogenesis agents that target VEGF signaling (e.g., sunitinib, sorafenib, bevacizumab). We tested the hypothesis that the hypoxia-activated prodrug (HAP) TH- 302, currently in phase 1/2 trials for the treatment of cancer, would exhibit enhanced efficacy in the context of an antiangiogenic- mediated increase in tumor hypoxia and potentiate the antitumor efficacy of the antiangiogenic. To characterize sunitinib-induced effects on tumor vasculature and tumor hypoxia, 786-O (RCC) and H460 (NSCLC) human ectopic tumor xenografts were treated with sunitinib (20 or 40 mg/kg) daily for 5 days and then 72 hours later animals were injected with pimonidazole to label hypoxic cells and Hoechst 33342 to label vascular perfusion. The NSCLC model (H460) exhibits a baseline hypoxic fraction of 7%. Sunitinib induced a dose-dependent increase in tumor hypoxia volume (24 ± 3.2% with 40 mg/kg vs. 7.3 ± 3.8% with Vehicle, p