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Tumor Microenvironment

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 fatty 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.

Faculty

Adjunct Faculty

  • Randy Burd, PhD
    Assistant Professor, University of Arizona
  • Yaacov Richard Lawrence, MD
    Director, Center for Translational Research in Radiation Oncology
    Sheba Medical Center, Tel HaShomer Hospital
    Tel Aviv University, Tel Aviv, Israel
  • Languino, Lucia
    Professor, Cancer Biology
  • Zhang, Jianke
    Associate Professor, Microbiology & Immunology
  • Karen Knudsen, PhD 
    Professor, Cancer Biology
  • Ullrich Rodeck, MD
    Professor of Dermatology

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.