Modulation of Therapeutic ResponseIn the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The major goal of this project is to define and understand those aspects of tumor physiology, including cellular and molecular processes that ultimately define the very nature of a tumor such that a particular dose of ionizing radiation, when used will be more effective. One means to that end is to investigate the interaction of ionizing radiation with a variety of chemotherapy and molecularly targeted agents to assess if tumors can be made more sensitive. Our current focus is on halofuginone. Halofuginone, an inhibitor of TGF beta, exhibits cytotoxicity and radiosensitization to a variety of different types of human tumor cell lines. This agent is of particular interest in that halofuginone has been shown to protect against radiation-induced late effects in normal tissues. We have shown that halofuginone does not protect SCC tumors against radiation-induced regrowth delay. Our pre-clinical studies support the concept that halofuginone will provide selective radioprotection of normal tissues with perhaps sensitization of tumor. Additionally we have shown that pheonoxodiol is a potent radiation sensitizer and we are presently conducting mechanistic and animal studies to further characterize this agent. Another major goal of this project is to develop functional imaging techniques to better characterize factors important in the tumor microenvironment that may prevent or diminish agents from impacting radiation response. It is well established that hypoxia is a major determinant of radiation sensitivity. Therefore, we are using several murine tumor models to study tumor hypoxia. Our approach is to use current invasive techniques and extend that information to non-invasive methods that are under development, such that patient tumor treatment profiles may optimized on an individual basis. Using novel magnetic resonance imaging equipment (EPR) developed in the Radiation Biology Branch we have recently shown that non-invasive tissue oxygen concentration can be evaluated in mice. In order to compare our EPR oxygen imaging data with other oxygen imaging techniques, we conducted a series of small animal PET studies using radioactive hypoxic-specific probes. Preliminary data indicate that neither Cu-64-ATSM nor F18-Miso accurately measure changes in tumor oxygenation. These data, while not useful to compare to our EPR data are important given that both agents are currently in clinical trials to determine tumor hypoxia in patients. Our EPR non-invasive functional imaging approaches should enhance our ability to better understand the tumor microenvironment and develop strategies to effectively attack potential barriers that currently limit the effectiveness of cancer treatment modalities.