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.
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.
|Bobko, Andrey A; Evans, Jason; Denko, Nicholas C et al. (2017) Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models. Cell Biochem Biophys 75:247-253|
|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|
|Golias, Tereza; Papandreou, Ioanna; Sun, Ramon et al. (2016) Hypoxic repression of pyruvate dehydrogenase activity is necessary for metabolic reprogramming and growth of model tumours. Sci Rep 6:31146|
|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|
|Verras, Meletios; Papandreou, Ioanna; Denko, Nicholas C (2015) WNT16-expressing Acute Lymphoblastic Leukemia Cells are Sensitive to Autophagy Inhibitors after ER Stress Induction. Anticancer Res 35:4625-31|
|Papandreou, Ioanna; Verras, Meletios; McNeil, Betina et al. (2015) Plant stilbenes induce endoplasmic reticulum stress and their anti-cancer activity can be enhanced by inhibitors of autophagy. Exp Cell Res 339:147-53|
|Cerniglia, George J; Dey, Souvik; Gallagher-Colombo, Shannon M et al. (2015) The PI3K/Akt Pathway Regulates Oxygen Metabolism via Pyruvate Dehydrogenase (PDH)-E1? Phosphorylation. Mol Cancer Ther 14:1928-38|
|Laderoute, Keith R; Calaoagan, Joy M; Chao, Wan-ru et al. (2014) 5'-AMP-activated protein kinase (AMPK) supports the growth of aggressive experimental human breast cancer tumors. J Biol Chem 289:22850-64|
|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|
|Denko, Nicholas C (2014) Hypoxic regulation of metabolism offers new opportunities for anticancer therapy. Expert Rev Anticancer Ther 14:979-81|
Showing the most recent 10 out of 11 publications