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.

Public Health Relevance

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).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA067166-16A1
Application #
8476677
Study Section
Special Emphasis Panel (ZCA1-RPRB-2 (J1))
Program Officer
Bernhard, Eric J
Project Start
1997-04-01
Project End
2018-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
16
Fiscal Year
2013
Total Cost
$1,600,018
Indirect Cost
$582,255
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Bobko, Andrey A; Evans, Jason; Denko, Nicholas C et al. (2016) Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models. Cell Biochem Biophys :
Zeidan, Youssef H; Xiao, Nan; Cao, Hongbin et al. (2016) Botulinum Toxin Confers Radioprotection in Murine Salivary Glands. Int J Radiat Oncol Biol Phys 94:1190-7
Jiang, Dadi; Lynch, Connor; Medeiros, Bruno C et al. (2016) Identification of Doxorubicin as an Inhibitor of the IRE1α-XBP1 Axis of the Unfolded Protein Response. Sci Rep 6:33353
Vilalta, Marta; Rafat, Marjan; Graves, Edward E (2016) Effects of radiation on metastasis and tumor cell migration. Cell Mol Life Sci 73:2999-3007
Rankin, Erinn B; Giaccia, Amato J (2016) Hypoxic control of metastasis. Science 352:175-80
Sun, Ramon C; Koong, Albert; Giaccia, Amato et al. (2016) Measuring the Impact of Microenvironmental Conditions on Mitochondrial Dehydrogenase Activity in Cultured Cells. Adv Exp Med Biol 899:113-20
Leszczynska, Katarzyna B; Göttgens, Eva-Leonne; Biasoli, Deborah et al. (2016) Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1. Sci Rep 6:21698
Olcina, Monica M; Giaccia, Amato J (2016) Reducing radiation-induced gastrointestinal toxicity - the role of the PHD/HIF axis. J Clin Invest 126:3708-3715
Alagappan, Muthuraman; Jiang, Dadi; Denko, Nicholas et al. (2016) A Multimodal Data Analysis Approach for Targeted Drug Discovery Involving Topological Data Analysis (TDA). Adv Exp Med Biol 899:253-68
LaGory, Edward L; Giaccia, Amato J (2016) The ever-expanding role of HIF in tumour and stromal biology. Nat Cell Biol 18:356-65

Showing the most recent 10 out of 177 publications