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
Vilalta, Marta; Brune, Jourdan; Rafat, Marjan et al. (2018) The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration. Clin Exp Metastasis 35:247-254
Tandon, Neha; Thakkar, Kaushik N; LaGory, Edward L et al. (2018) Generation of Stable Expression Mammalian Cell Lines Using Lentivirus. Bio Protoc 8:
Yang, Zhifen; Zhang, Jing; Jiang, Dadi et al. (2018) A Human Genome-Wide RNAi Screen Reveals Diverse Modulators that Mediate IRE1?-XBP1 Activation. Mol Cancer Res 16:745-753
Benej, Martin; Hong, Xiangqian; Vibhute, Sandip et al. (2018) Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci U S A 115:10756-10761
Rafat, Marjan; Aguilera, Todd A; Vilalta, Marta et al. (2018) Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients. Cancer Res 78:4241-4252
Saiki, Julie P; Cao, Hongbin; Van Wassenhove, Lauren D et al. (2018) Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes. Proc Natl Acad Sci U S A 115:6279-6284
Olcina, Monica M; Kim, Ryan K; Melemenidis, Stavros et al. (2018) The tumour microenvironment links complement system dysregulation and hypoxic signalling?. Br J Radiol :20180069
Peinado, H├ęctor; Zhang, Haiying; Matei, Irina R et al. (2017) Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17:302-317
Vilalta, Marta; Hughes, Nicholas P; Von Eyben, Rie et al. (2017) Patterns of Vasculature in Mouse Models of Lung Cancer Are Dependent on Location. Mol Imaging Biol 19:215-224
Boyko, Tatiana V; Bam, Rakesh; Jiang, Dadi et al. (2017) Inhibition of IRE1 results in decreased scar formation. Wound Repair Regen 25:964-971

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