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 was initiated with this compound with myself as the Pricipal Investigator.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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010849-06
Application #
8552862
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2012
Total Cost
$406,583
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Urick, Mary Ellen; Chung, Eun Joo; Shield 3rd, William P et al. (2011) Enhancement of 5-fluorouracil-induced in vitro and in vivo radiosensitization with MEK inhibition. Clin Cancer Res 17:5038-47
Kelly, Ronan J; Lopez-Chavez, Ariel; Citrin, Deborah et al. (2011) Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin. Mol Cancer 10:35
Mitchell, James B; Choudhuri, Rajani; Fabre, Kristin et al. (2010) In vitro and in vivo radiation sensitization of human tumor cells by a novel checkpoint kinase inhibitor, AZD7762. Clin Cancer Res 16:2076-84
Citrin, Deborah; Camphausen, Kevin; Wood, Bradford J et al. (2010) A pilot feasibility study of TNFeradeâ„¢ biologic with capecitabine and radiation therapy followed by surgical resection for the treatment of rectal cancer. Oncology 79:382-8
Chung, Eun Joo; Brown, Aaron P; Asano, Hiroaki et al. (2009) In vitro and in vivo radiosensitization with AZD6244 (ARRY-142886), an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 kinase. Clin Cancer Res 15:3050-7
Brown, Aaron P; Wendler, David S; Camphausen, Kevin A et al. (2008) Performing nondiagnostic research biopsies in irradiated tissue: a review of scientific, clinical, and ethical considerations. J Clin Oncol 26:3987-94