Tumor hypoxia has been recognized as a hindrance to successful radiation therapy for over 50 years. Attempts to overcome this obstacle by delivering more oxygen to the tumor, however, have been clinically disappointing, largely due to the functional limitations of the tumor vasculature. 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 increase overall functional oxygenation. Commonly prescribed anti-diabetic biguanidedrugs (metformin, phenformin) have been shown to reduce mitochondrial function in vitro at least in part through inhibition of electron transport chain (ETC) complex 1. We propose to test the hypothesis that pharmacologic downregulation of mitochondrial metabolism will reduce cellular demand for oxygen and result in decreased tumor hypoxia and specific radiosensitization of model tumors. This approach will be especially effective when using hypofractionated radiation protocols where oxygen enhancement can have a profound effect on overall tumor cell killing. We have organized this proposal into the following four specific aims. 1) Determine the role of tumor suppressor LKB1 in mediating the effect of biguanides on mitochondrial metabolism. 2) Establish the relative importance of glucose versus glutamine as a mitochondrial fuel in regulating mitochondrial response to intervention with biguanides. 3) Quantitate the biochemical effect of biguanides on mitochondrial function, tumor hypoxia, and glucose consumption in vivo. And 4) Establish the optimal level of radiosensitization in both subcutaneous and orthotopic model tumors treated with biguanides and radiation. It is important to note that because normal tissue is typically well oxygenated, thi systemic approach will specifically radiosensitize tumors, without causing enhanced normal tissue toxicity.

Public Health Relevance

This proposal investigates the potential use of an existing family of drugs to make tumors sensitive to radiation. At the completion of the work, we should be able to decide if this approach is feasible. We will determine if this approach is ready for translating into a clinical trial. We will have insight into which tumors would be candidates for such a treatment, what compound would be most likely to succeed, and how the drug and radiation should be combined. We will also know if we can use functional PET imaging as a secondary endpoint in such a trial, and if the response in imaging can predict clinical response in the patient.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA163581-02S1
Application #
8700567
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Ogunbiyi, Peter
Project Start
2012-09-25
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$91,264
Indirect Cost
$31,825
Name
Ohio State University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210