Translational research in radiation-induced DNA damage signaling and repair

Radiotherapy is an effective tool in the fight against cancer. It is non-invasive and painless, and with advanced tumor imaging and beam control systems, radiation can be delivered to patients safely, generally with minor or no adverse side effects, accounting for its increasing use against a broad range of tumors. Tumors and normal cells respond to radiation-induced DNA damage by activating a complex network of DNA damage signaling and repair pathways that determine cell fate including survival, death, and genome stability. DNA damage response (DDR) proteins represent excellent targets to augment radiotherapy, and many agents that inhibit key response proteins are being combined with radiation and genotoxic chemotherapy in clinical trials. This review focuses on how insights into molecular mechanisms of DDR pathways are translated to small animal preclinical studies, to clinical studies of naturally occurring tumors in companion animals, and finally to human clinical trials. Companion animal studies, under the umbrella of comparative oncology, have played key roles in the development of clinical radiotherapy throughout its >100-year history. There is growing appreciation that rapid translation of basic knowledge of DNA damage and repair systems to improved radiotherapy practice requires a comprehensive approach that embraces the full spectrum of cancer research, with companion animal clinical trials representing a critical bridge between small animal preclinical studies, and human clinical trials.