In Vivo Validation Of Candidate Radiosensitizers That Target Ionizing Radiation Induced Foci

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Even after several decades of use, radiation therapy (RT) remains an important tool in the treatment of different types of cancers. Discovery of novel non-toxic radiosensitizers that halt tumor growth and/or restore senescence checkpoint growth arrest are highly desirable. Our work, along with other studies, has revealed that disrupting the repair of DNA double strand breaks (DSBs) can sensitize cancer cells to genotoxic stress. In our prior work we used GFP-53BP1 expressed in the MCF-7 breast cancer cell line as a sensor to screen small molecules that affect radiation-induced foci (IRIF) persistence. The screening of libraries of approved and investigational drugs identified several “hits”, a surprising number of which were compounds without known connections to the DNA damage response or to chromatin alteration. Significantly, several compounds that promote IRIF persistence also restore the senescence checkpoint in irradiated cancer cells. To validate the candidate radiosensitizers we demonstrated that selected hits induced IRIF persistence and senescence in a variety of different cell lines, including HNSCC, and pancreatic and melanoma cells. Based on in vitro analysis, we identified the most promising compounds/”hits” for testing in tumor growth studies. Combining selected “hits” with radiation treatment (RT) induced IRIF persistence and increased senescence induction in MCF7-GFP-53BP1 xenografts growing in nude mice. We report that drug “hits” combined with RT induced senescence and suppressed tumor regrowth in highly radioresistant B16-SIY melanoma tumors growing in syngeneic C57BL/6 mice. Our data suggest that the use of nontoxic radiation sensitizers which enhance the effects of DNA damage and overcome intrinsic tumor radioresistance may be employed to enhance the therapeutic ratio of radiotherapy. Citation Format: Elena V. Efimova, Helena J. Mauceri, Edwardine Labay, Harold Sutton, Ashly Haraf, Stehen J. Kron, Ralph Weichselbaum. In vivo validation of candidate radiosensitizers that target ionizing radiation induced foci. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-178. doi:10.1158/1538-7445.AM2014-LB-178