A number of agents have begun testing for this project. One agent, a MEK inhibitor, has been evaluated as a radiation sensitizer both in vitro and in vivo. The agent was found to sensitize three histologies to radiation in vitro and to sensitize two tested cell lines to radiation in subcutaneous xenografts. Additional mechanistic work has revealed that the cause of this senstization appears to be related to abrogation of the G2 checkpoint after irradiation. Additional work with this compound is focusing on possible biomarkers of effect to identify candidate markers of efficacy for clinical translation. In addition, the agent was comined with chemotherapy and additional sensitization to radiation was seen, supporting the conduct of a clinical trial. A clinical trial has recently been initiated with this compound with myself as the Pricipal Investigator. Two additional agents are currently undergoing testing for efficacy as radiation sensitizers. These include a small molecule poly(ADP-ribose) polymerase (PARP) inhibitor and a multi-target tyrosine kinase inhibitor. The preliminary in vitro clonogenic assays have been promising for these two compounds. Additional in vitro work, in vivo work, and mechanistic work will be ongoing. The eventual goal for these compounds is clinical translation into trials as radiation sensitizers. In additon, the PI has been active in translating findings from collaborators in the Radiation Biology Branch inot clinical trials.
