Utilizing Radiation-Induced Multi-potency to Increase the Efficacy of Radiotherapy

SUMMARY/ABSTRACT Radiation therapy (RT) is an integral part of the standard-of-care against glioblastoma (GBM). While the addition of RT to surgery over surgery alone significantly prolongs patient survival, all patients with GBM ultimately succumb to the disease and survival times are unacceptably low. So far, the addition of targeted or non-targeted therapies to surgery and RT have had limited success and indicate the need for novel strategies against this disease. There is ample evidence supporting the heterogeneity of GBM and the existence of a small population of glioblastoma stem cells (GSCs)), relatively resistant to RT and chemotherapy, and able to regrow the tumor. Together, treatment resistant GSCs, dispersion of cancer cells beyond the visible tumor, large areas of hypoxia and the blood-brain-barrier (BBB) add to the challenge GBM presents to cancer therapy. We have previously demonstrated that radiation reactivates stem cell programs causing cellular multipotency and plasticity, followed by the acquisition of an induced GSC state. Importantly, we showed that this process could be targeted and that preventing the induction of GSCs led to improved survival in animal models of GBM. We have now developed novel compounds that cross the BBB and prevent the radiation-induced generation of GSCs. Furthermore, our preliminary data indicate that a radiation-induced multipotent state can be utilized to allow for terminal differentiation of GBM cells. The studies proposed in this application build on these findings and take the research program into this exciting new direction to utilize this induced multipotent state for altering the radiation responses of GBM.