Improving Radiation Therapy in Pancreatic Cancer Through Radiosensitization Strategies

Radiation therapy (RT) is a mainstay of treatment for a myriad of cancers; however, it remains a controversial option in the management of patients with pancreatic cancer. The prognosis for this disease remains one of the poorest, despite recent advances in chemotherapy, which still has limited efficacy and suffers from multiple forms of resistance. The application of RT in patients with pancreatic cancer remains largely institution and provider dependent. Despite advances in RT where higher doses can be delivered while sparing adjacent normal organs, local control remains a problem, highlighting the necessity for improvements in the current RT approach. Emerging strategies are currently being developed with the aim of improving the effects of RT using "radiosensitization" mechanisms. The objective of radiosensitization is to either enhance DNA damage induced by RT or to prevent its repair or to impair the RT-resistance-associated components of the tumor. The process of radiosensitization can be achieved through the use of conventional chemotherapy agents or by novel molecules that inhibit DNA damage response effectors, as well as cell cycle checkpoints. Additionally, nanoparticles with a high atomic number have the potential to act as radiosensitizers by enhancing the effects of RT specifically in tumor cells. Another avenue of radiosensitization entails the combination of immunotherapy with immune checkpoint inhibitors to increase the immunomodulatory impact of RT. The radiosensitivity of pancreatic ductal adenocarcinoma may also be enhanced by targeting components of the tumor microenvironment or metabolic characteristics associated with resistance to RT. This review aims to provide a comprehensive overview of cutting-edge radiosensitization strategies, from their initial preclinical studies to their current status in clinical trials.