Radiation-induced molecular targets

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The long-standing focus of our laboratory program involves the radiation and microenvironmental stress response. We are now focusing on "radiation inducible targets" that is, exploring the use of multi-fractionated (MF) radiation as well as higher single doses (SD) to induce a cellular phenotype that makes the cell susceptible for molecular targeted therapy and immunotherapy. In essence, radiation would set up the tumor for enhanced drug killing and enhanced immune response. This project has now demonstrated that different dose sizes of radiation- MF and SD - (10 Gy x1, 2 Gy x5, 1 Gy x10 and down to 0.5 Gy x 10) produce different phenotypes. We have demonstrated that the cells post-radiation are more drug sensitive to a drug post-radiation than before at 1 week and up to 3 months later, indicating stable adaptation. This is applicable to drugs available for clinical use. We are now working with experts in complex systems analysis to identify pathways to target and working on timing of radiation and drug(s). With the major interest in immune modulation, our work has significant bearing on the dose and fractionation of radiation that can be exploited for immune enhancement for tumor control, including direct and abscopal effects. We are working with Jim Mitchell of RBB and Murali Cherukuri of RBB who has hyperpolarized MRI techniques to study metabolic adaptation. Closely related to this work are efforts being done on identifying biomarkers and machanisms of radiation injury. This relates to work I do in the Administration for Strategic Preparedness and Response in Health and Human Services (HHS). We are working on the potential of bringing these mitigators into cancer care.