The major goals of this project have been to advance genetic and molecular based knowledge of hypoxia induced gene and protein regulation to understand tumor progression and develop more targeted therapeutics for solid tumors. The four projects and two cores that comprise this grant explore how to protect normal tissues to increase the efficacy of hypofractionated and fractionated radiotherapy, and how to specifically increase tumor radiosensitivity by manipulating mitochondrial metabolism and the unfolded protein response pathways. These projects represent a highly integrated effort to translate our understanding of the biology of hypoxia and metabolism to enhance the efficacy of radiotherapy. The first two projects, Project 1 (Project Leader: Giaccia) and Project 2 (Project Leader: Le), wil attempt to mitigate the effects of radiation on the Gl tract and submandibular glands through the exploitation of the PHD/VHL/HIF pathway and metabolic activation of aldehyde dehydrogenase (ALDH3A2). During the last grant period, Project 1 (Project Leader: Giaccia) was focused on the role of CTGF and Lysyl Oxidase in pancreatic growth and metastasis. This project has been quite successful and resulted in a Phase I clinical trial for anti-CTGF in pancreatic cancer. Similarly, Project 2 (Project Leader: Le) has focused her project on using activation of ALDH3A2 to protect and mitigate radiation-induced toxicity to the submandibular gland. This is a new direction from the last submission where she was highly productive in understanding the role of hypoxia induced Osteopontin (OPN) on tumor growth and metastasis. Project 3 (Project Leader: Denko) and Project 4 (Project Leader: Koong) are continuations of the projects from the last grant period and will investigate how manipulating mitochondrial activity and the UPR pathway will increase radiosensitivity and work cooperatively with radiotherapy to control tumor growth, respectively. Both of these projects are also highly translational and have had significant achievements during the last funding cycle. In the competitive renewal, Project 3 will investigate whether correcting the oxygen supply and demand mismatch through the use of papaverine will increase tumor oxygenation and radiosensitivity. If successful, this molecule, which has already been approved clinically as anti-spasmodic, could rapidly enter clinical trial. Project 4 identifie new inhibitors of the IRE1 endonuclease, which controls one branch of the unfolded protein response, and sensitizes hypoxic cells to radiation. The overall hypothesis to be tested in this PPG is whether manipulating hypoxia response pathways will result in increased tumor control and normal tissue protection.
The concept of therapeutic index has two components: the tumor component and the normal tissue component. However, manipulation of either part of this equation can increase the therapeutic index. This program project grant is focused on increasing the therapeutic index of radiotherapy by reducing radiation induced normal tissue toxicity (Projects 1 and 2) and increasing tumor radiosensitivity (Projects 3 and 4).
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