Poster abstracts

Poster number 70 submitted by Abigail Zalenski

Targeting KIF11 to Radiosensitize Glioblastoma and Decrease Cell Invasion

Abigail Zalenski (Dept. of Neuroscience), Miranda Montgomery (Dept. of Radiation Oncology), Kuntal De (Dept. of Radiation Oncology), Treg Grubb (Dept. of Radiation Oncology), Monica Venere (Dept. of Radiation Oncology)

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 xenograph GBM mouse model increases survival. However, in this model, tumors recurred after treatment was stopped, indicating that this 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 increases cell death over either monotherapy. We also previously demonstrated that KIF11 is a driver of invasion in GBM, possibly by coordinating with the Kinesin-1/CRMP2 complex. In this study, we explored a model where KIF11 potentially coordinates with CRMP2 and its binding partner, Kinesin-1, to drive GBM cell invasion. By depleting KIF11, CRMP2, and Kinesin-1, and use a variety of invasion/migration assays we determined that depletion of CRMP2 and Kinesin-1 had a similar impact on cell invasion to depleting KIF11. Our proposed work has identified a new form of treatment for patients with GBM, and has begun to elucidate the mechanism by which KIF11 drives GBM cell invasion.

Keywords: glioblastoma, cancer stem cell, radiotherapy