Solid tumors exist in an extremely hostile environment for cell growth. As even the smallest tumors growthey rapidly outstrip new blood vessel formation leading to poor perfusion and hypoxia. Cancer cells adaptby changes in key cell survival signaling pathways leading to an increased glycolytic metabolism, resistanceto apoptosis, and the production of factors that increase angiogenesis. Cancer cells frequently also developconstitutive upregulation of the genes regulating the hypoxia response leading to rapidly growing tumors witha poor patient prognosis. These changes also make tumors resistant to radiation and chemotherapy, and area major reason for the failure of cancer therapy. The hypothesis upon which our studies are based is that thesignaling pathways that regulate the growing tumor's response to hypoxia provide novel targets for thedevelopment of agents to selectively treat solid tumors. The pathways we will study are thephosphoinositide-3-kinase cell survival signaling pathway,the thioredoxin-1 redox signaling stress pathwayand the hypoxia mediated increase in redox sensitive transcription factors. The most studied hypoxiainduced transcription factor is the hypoxia inducible factor-1 (HIF-1), a heterodimer of a hypoxia induciblesubunit and HIF-1(3. We have developed a novel inhibitor of HIF-1a, PX-478, which shows remarkablesingle agent antitumor activity in animaj studies and synergy with radiation We will conduct a Phase I trial ofPX-478 together with radiation in patients with metastatic cancer to the bone employing molecular imagingand other molecular markers to assess drug effect and early patient response. We have also developed anovel inhibitor of Ptdlns-3-K, PX-866, that also inhibits HIF-1 a and the hypoxia response and will conduct asecond clinical trail in later years of the grant. While HIF-1 is an important mediator of the hypoxic response,it is not the only transcription factor involved. We have used transcription factor profiling to identify two othertranscription factors, Sp1 and Nrf2, that play an independent role in the hypoxia response and will study theirmechanisms of action. The objective of our work is to understand the mechanisms of hypoxia induced geneexpression that will allow the development of strategies and new drugs for treating cancer.
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