Exth-38. Targeting Kif11 to Radiosensitize Glioblastoma

Abstract

Glioblastoma (GBM) is the most lethal primary brain tumor, with a 5 year survival rate of only 5%. The standard of care for GBM is maximal surgical resection of the tumor, followed by irradiation and chemotherapy. Despite treatment, tumors recur in almost 100% of patients. There are subpopulations of cells in GBM that are radioresistant and chemoresistant, and new treatments will need to inclusively target these cells. KIF11 is a mitotic protein that drives bipolar spindle formation and is crucial for successful completion of mitosis. We previously reported that KIF11 is overexpressed in GBM over normal brain tissue, and that inhibiting KIF11 in a patient-derived xenograft (PDX) GBM mouse model increased survival. However, in this model, tumors recurred after treatment was stopped, indicating that treatment may have had a cytostatic effect, rather than cytotoxic. Importantly, it has been reported that cells are most vulnerable to irradiation when they are in mitosis. Because using a KIF11 inhibitor arrests cells in mitosis, we hypothesized that combining irradiation and a KIF11 inhibitor would radiosensitize GBM cells, and lead to greater tumor cell death. In this study, we found that combination therapy increased cell death over vehicle or either treatment used alone in patient-derived GBM cells in vitro. Additionally, we found that inhibiting KIF11 combined with radiotherapy increased survival over vehicle or monotherapy in orthotopic PDX models. Our results demonstrate that combining KIF11 inhibitors with radiotherapy is a promising potential therapy for GBM.