Altering the response to radiation: radiosensitizers and targeted therapies in pancreatic ductal adenocarcinoma: preclinical and emerging clinical evidence

Radiation therapy continues to have an evolving role in pancreatic ductal adenocarcinoma. While metastatic failure likely contributes to the majority of patient mortality, achieving local control through surgery and/or radiation appears to be important as certain studies suggest that mortality is contributed by local failure. Many studies support that pancreatic cancer is a relatively radiation resistant tumor type. In addition, the ability to further improve radiation through dose escalation strategies in the non-metastatic setting is hampered by closeness of normal organs, including small bowel and stomach, to the tumor. Thus subverting molecular pathways that promote radiation resistance will be critical to further success of radiation in this disease. There is a wealth of preclinical data supporting the targeting of various molecular pathways in combination with radiation therapy, including DNA repair, cell cycle checkpoint proteins, receptor tyrosine kinases, oncoproteins, stem cells, and immunomodulation. A number of clinical trials have been completed or are on-going with novel molecular inhibitors. In this review, we summarize existing preclinical and clinical molecular strategies for improving the efficacy of radiation in pancreatic cancer, and highlight recent and ongoing clinical trials combining radiation and various targeted therapies.