STEM-22. TARGETING KIF11 TO RADIOSENSITIZE GLIOBLASTOMA

Abstract

Abstract Glioblastoma (GBM) is the most common primary brain tumor, and is incredibly lethal, with less than 10% of patients surviving more than 5 years after diagnosis. These tumors are routinely treated with radiotherapy, although we and others have shown that there is a subpopulation of GBM cells, called cancer stem-like cells (CSCs), that are radio-resistant, and do not respond to this standard therapy. We aim to overcome the radio-resistance of GBM CSCs by using radiotherapy in combination with a KIF11 inhibitor. We previously reported that the mitotic kinesin KIF11, required for bipolar spindle formation during mitosis, is elevated in GBM and portends poor prognosis. We also demonstrated that invasiveness and self-renewal of CSCs could be targeted with ispinesib, a small molecule inhibitor to KIF11. Furthermore, survival of mice bearing orthotopic glioblastoma was prolonged with KIF11 inhibition, although tumor burden increased with cessation of treatment. To combat tumor recurrence after treatment cessation, we proposed to use a KIF11 inhibitor with radiotherapy. KIF11 inhibitors will arrest cells in G2/M, where they are most sensitive to radiotherapy. By enriching CSCs in G2/M, we hypothesized that we would overcome CSC radio-resistance to decrease CSC viability and improve survival. We first tested the efficacy of combining a KIF11 inhibitor and irradiation in vitro. We found that using combination therapy to treat CSCs significantly decreased CSC survival over vehicle or either treatment used as a monotherapy. We then investigated the effects of combination therapy in vivo. Using a KIF11 inhibitor combined with irradiation increased survival of mice bearing orthotopic glioblastoma. Our results suggest that targeting KIF11 in combination with radiotherapy is a promising technique to overcome the radio-resistance of CSCs, and holds potential to significantly improve treatment outcomes and extend survival of patients with GBM.