Tumor hypoxia has been recognized as a hindrance to successful radiation therapy for over 50 years. The search for small molecules to act as oxygen mimetics and selectively sensitize hypoxic tumors to radiotherapy has had many worthy candidates in the past, but none have been successful in Phase III clinical trials. In addition, attempts to overcome hypoxia by delivering more oxygen to the tumor, however, have been clinically disappointing, largely due to the functional limitations of the tumor vasculature. Increasing systemic oxygen delivery does not result in increased tumor oxygenation. Instead of reducing hypoxia by increased delivery of oxygen, this application proposes to limit hypoxia by reducing oxygen consumption within the tumor. If the supply of oxygen delivered to the tumor is constant, then transient reduction in demand will result in increased tumor oxygenation. We have identified several commonly prescribed drugs (papaverine is the lead compound) that dramatically reduce mitochondrial function in vitro. We propose to test the hvpothesis that pharmacologic down regulation of mitochondrial metabolism will reduce cellular demand for oxygen and result in decreased tumor hypoxia and radiosensitization of model tumors. This approach will be especially effective when added to hypofractionated radiation protocols where oxygen enhancement can result in a profound increase on overall tumor cell killing. We have organized this proposal into the following four specific aims. 1) Determine the effective concentration of two mechanistically different, FDA approved drugs to inhibit the mitochondrial function of a panel of cancer cell lines in vitro. 2) Quantify the biochemical effect of drug treatment on mitochondrial function, tumor hypoxia, and glucose consumption in model tumors with Core B. 3) Establish the optimal level of radiosensitization in both subcutaneous and orthotopic model tumors treated with metabolic modifiers in collaboration with Project 1 and 4, and 4) Initiate a clinical trial that directly measures tumor oxygenation changes in patients with advanced Head and Neck Squamous Cell Carcinomas (HNSCC) with Project 2. It is important to note that because normal tissue is typically well oxygenated, systemic delivery of well tolerated metabolic modifiers will specifically radiosensitize tumors, without causing enhanced normal tissue toxicity.

Public Health Relevance

Almost half of all human cancers receive some type of radiotherapy as part of their treatment. However, tumors vary considerably in their sensitivity to radiation, due in part the amount of oxygen present We propose to make tumors more radiation sensitive by increasing oxygen levels within the tumor. We will repurpose FDA approved drugs for this novel application. We will test model tumors in mice for increased radiation sensitivity, and patient tumors for increased oxygenation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA067166-17
Application #
8744822
Study Section
Special Emphasis Panel (ZCA1-RPRB-2)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
17
Fiscal Year
2014
Total Cost
$195,957
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Rankin, Erinn B; Fuh, Katherine C; Castellini, Laura et al. (2014) Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A 111:13373-8
Kariolis, Mihalis S; Miao, Yu Rebecca; Jones 2nd, Douglas S et al. (2014) An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis. Nat Chem Biol 10:977-83
Taniguchi, Cullen M; Miao, Yu Rebecca; Diep, Anh N et al. (2014) PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2. Sci Transl Med 6:236ra64
Xiao, Nan; Lin, Yuan; Cao, Hongbin et al. (2014) Neurotrophic factor GDNF promotes survival of salivary stem cells. J Clin Invest 124:3364-77
Sun, Ramon C; Denko, Nicholas C (2014) Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab 19:285-92
Giaccia, Amato J (2014) Molecular radiobiology: the state of the art. J Clin Oncol 32:2871-8
Finger, E C; Cheng, C-F; Williams, T R et al. (2014) CTGF is a therapeutic target for metastatic melanoma. Oncogene 33:1093-100
Kuo, Peiwen; Bratman, Scott V; Shultz, David B et al. (2014) Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response. Clin Cancer Res 20:5558-69
Vilalta, Marta; Rafat, Marjan; Giaccia, Amato J et al. (2014) Recruitment of circulating breast cancer cells is stimulated by radiotherapy. Cell Rep 8:402-9
Razorenova, Olga V; Castellini, Laura; Colavitti, Renata et al. (2014) The apoptosis repressor with a CARD domain (ARC) gene is a direct hypoxia-inducible factor 1 target gene and promotes survival and proliferation of VHL-deficient renal cancer cells. Mol Cell Biol 34:739-51

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