Tumor response to therapy and probability of metastases greatly depends on the tumor microenvironment, which in turn has a complex interrelationship with tumor metabolism. The important factors involved are tumor oxygen levels, access to metabolites and pH, all of which influence the tumor:normal tissue therapeutic ratio after most treatment agents. Drs. Wachsberger, Coss and Leeper in association with Dr. Jerry Glickson, director of the Molecular Imaging Division, University of Pennsylvania. Dr. Glickson performs small animal MRI and MRS for measuring tumor hypoxia and metabolism using H-1, P-31, C-13, O-17, T1<rho> and DCE. With the generous support of NCI, we have developed a large translational program manipulating tumor oxygen levels and tumor pH to sensitize xenografts to radiation, chemotherapy and hyperthermia.
The importance of tumor metabolism is only now being recognized for its important role influencing tumor therapeutic response. For instance the role of tumor glycolysis, mitochondrial oxidation, beta-oxidation of fattly acids and lactate metabolism are under intense investigation nationwide. Within the year, a clinical trial using metaiodobenzylguanidine (MIBG) plus excess glucose to inhibit tumor mitochondrial respiration, thus leading to tumor acute acidification and tumor oxygenation, to sensitize melanomas in-transit and soft tissue sarcomas of the limb to chemotherapy will be instituted in collaboration with the Department of Surgery, Hospital of the University of Pennsylvania.
- Adam Dicker, MD, PhD
Professor, Chairman and Director, Experimental Radiation Oncology Division
- Bo Lu, MD, PhD
Professor, Director, Division of Molecular Radiation Biology
- Dennis B. Leeper, PhD
Professor and Founding Director
- Ullrich Rodeck, MD
Professor of Dermatology
- Phyllis R. Wachsberger, PhD
- Richard Lawrence, MD
- George Iliakis, PhD
Professor, University of Essen, DL
- Andrew J. Milligan, Jr, PhD
Professor, President of Bionix Medical Technologies
- Ya Wang, MD, PhD
Professor, Emory University
- Randy Burd, PhD
Assistant Professor, University of Arizona
Recent studies by Drs. Coss and Leeper have demonstrated that human melanoma cells growing at low pH can be sensitized to thermal therapy and radiotherapy by inhibition of the monocarboxylate transporters thereby inhibiting lactate export from the cell and inhibiting pyruvate import into the mitochondria. Not only are tumor cells acidified but also oxidative phosphorylation and ATP production are greatly reduced leading to energy deprivation and increased tumor oxygenation. Separate studies by Dr. Coss have found that 17AAG, an inhibitor of the HSP90 chaperone, is selectively toxic to tumor cells growing in an acidic environment. This inhibitor selectively sensitizes tumor cells growing at low pH to ionizing radiation. The mechanisms responsible for radiosensitization of tumor cells growing at low pH by 17AAG are being investigated. These mechanisms include, among others, inhibition of RAD51 and inhibition of HRR.