IOTF Fellowship Program # 3

Mentor:
Michael D. O'Hara, Ph.D.

Organizational Affiliation and Position:
FDA Staff Fellow, Radiation Biologist, Laboratory of Radiation Bioeffects, Division of Biology, Office of Science and Engineering Laboratories (OSEL), Center for Devices and Radiological Health (CDRH), FDA

Contact Information:
michael.ohara@fda.hhs.gov (301)796-0294

Title of Research Program:
Sensitization to Thermoradiotherapy in Human Melanoma Xenografts

Research Project Summary:
Tumor temperature elevation (hyperthermia) has been shown to increase the cytotoxicity of radiation therapy and some types of chemotherapy. A number of well designed and well executed positive clinical studies have started to re-new interest in the addition of hyperthermia to radiation therapy and or chemotherapy. A proposed further enhancement of this sensitizing effect of hyperthermia is to target the metabolism of tumors during thermoradiotherapy or thermochemotherapy to further increase tumor cytotoxicity. A wide variety of drugs with diverse methods of action have been proposed as modifiers of tumor metabolism. Many of these new exploratory multimodalty therapies will combine drugs with diverse mechanisms of action with medical device based therapies such as hyperthermia and radiation therapy. Safety and treatment efficacy may be an issue with some of these new multimodal therapies.

This project is performed in association with an NIH NCI sponsored program project awarded to Dr. Dennis B. Leeper at Thomas Jefferson University in Philadelphia entitled "Modification of Hyperthermia Response". The hypothesis will test whether acute tumor acidification by lactic acidosis will enhance thermoradiosensitization and selectively sensitize melanoma xenografts to radiotherapy. This project will use hyperglycemia to fuel lactic acid production in melanoma xenografts, the FDA approved tumor imaging agent, meta-iodobenzylguanidine (MIBG) to increase lactic acid production and the drug, Lonidimine to inhibit acid export out of tumor cells during thermoradiotherapy. The endpoint will be tumor growth delay after hyperthermia or radiation + hyperthermia. It is expected that these results will provide pre-clinical evidence of safety and efficacy for tumor acidification strategies and demonstrate their impact on the thermal and thermal radiotherapeutic response of human tumors.

Proposed Project for the IOTF Fellow:
The fellow will establish the most effective protocols for achieving maximal thermoradiosensitization by: 1. Induction of lactic acidosis by hyperglycemia alone; 2. Increased lactic acidosis and tumor oxygenation by inhibiting respiration by meta-iodobenzylguanidine (MIBG) or inhibiting lactate export by Lonidimine. The endpoint will be tumor growth delay after hyperthermia or radiation + hyperthermia. It is expected that these results will provide pre-clinical evidence of safety and efficacy for tumor acidification strategies and demonstrate their impact on the thermal and thermal radiotherapeutic response of human tumors.

Regulatory Activity:
Results and experimental design will be published to establish safety and efficacy of this proposed tumor therapy and open for discussion by interested parties, the methodological approach. The fellow will apply greater understanding of the impact of multimodality thermoradiosensitization on safety and efficacy to the Center's interest in all tumor types, other forms of radiation delivery (external beam, brachytherapy), methods of hyperthermia delivery (local, regional and whole body) as well as the agency's interest in new chemotherapy agents. In addition to published results, the fellow will aid Office of Device Evaluation scientist with development of industry guidance documents, pre-market approval submissions and clinical trial designs.