Most cancers develop and grow under stressful conditions of low oxygen availability. The adaptations to hypoxia involve: (1) upregulation of hypoxia signaling pathways, such as that involving hypoxia inducing factor; and (2) dysregulated production of reactive oxygen species (ROS). Both features lead to survival advantages in the cancer cells and lower their sensitivity to existing therapies. This application seeks to develop and clinically test therapies directed specifically to molecular targets involving hypoxia signaling (Project 1), ROS signaling (Project 2), and the development of methods and agents to image these conditions in tumors in vivo. At least three agents will be studied in early-stage, translational clinical trials, performed in Core D. Each trial will develop and evaluate novel molecular biomarkers (Core C) and in vivo imaging techniques (Project 3). Mechanistic hypothesis studies are performed via close interactions between the 3 projects and will undergo clinical validation testing through the trials performed under Core D. The Biometry Core Service, (Core B) will provide design and analysis support for both traditional clinical endpoints such as toxicity response and pharmacokinetics, as well as for validation of biomarker and mechanism of action-based imaging studies in animal models and in patients. The overall goal of this research grant is to identify entirely new molecular targets and develop agents to """"""""hit"""""""" those targets. There are two early-stage cancer drug companies which will provide clinical drug supplies for the trials, and the translational studies will be carried out within each project using patient specimens derived from the Phase I trials. These trials include: (1) the HIF-1a inhibitor PX-478 in patients with metastatic breast cancer and the PI-3 kinase, (HIF-1a signaling), inhibitor PX-866 in refractory cancers (Project 1); (2) ROS-generating small molecule imexon and one cyanoaziridine analog in patients with pancreatic cancer (Project 2); (3) early stage clinical trials of hypoxia and ROS-detecting agents and methods (Project 3). Interactions between the projects involve the testing of hypoxic agents from Project 1 in pancreas models (Project 2), the effects of ROS agents (Project 2), on hypoxia signaling pathways (Project 1), identification and selection of redox and hypoxia gene expression patterns as predictors of response (Projects 1 and 2), and the development and validation of hypoxia and ROS detecting methods developed in Project 3 in both Projects 1 and 2. ?
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