Targeting Therapy-Resistant Pancreatic Cancer Stem Cells Through Selective Sensitization and Radiation Therapy

Pancreatic cancer is the third leading cause of cancer death in the United States. Radiation therapy is frequently utilized to slow tumor growth and treat pancreatic cancer pain. However, due to high risk of duodenal toxicity, limited dosing allows for radioresistant disease progression. Using genetically engineered models of pancreatic cancer, and a newly developed reporter for the stem cell gene Musashi (Msi), we studied the radioresistance of Msi-expressing pancreatic cancer cells and their dsDNA break repair capacity. Furthermore, we designed novel strategy using biodegradable nanoparticles loaded with radiosensitizer to selective target this cell population both in vitro and in vivo. Here, we show that Msi expression identifies the population of pancreatic cancer cells that are highly resistant to radiation both in vitro and in vivo. This differential radioresistance is in part due to the fact that Msi2-expressing pancreatic cancer cells display enhanced capacity for dsDNA break repair in vivo compared to cells that do not express Msi2. To define new ways to target these radioresistant cells, we designed and delivered selective radiosensitizer loaded nanoparticles into Msi2+ tumor cells; this strategy enabled effective elimination Msi expressing cancer cells by making them highly vulnerable to low-dose radiotherapy in vivo. Collectively these data identify a novel therapeutic approach for eradicating radioresistant pancreatic cancer cells and improving control over this disease.