SC-32 * TARGETING PROLIFERATION AND INVASION IN GLIOBLASTOMA VIA MITOTIC KINESINS

Abstract

The nearly universal tumor recurrence seen in glioblastoma is driven by a myriad of factors including the invasive nature of the disease and a cellular heterogeneity that includes a more treatment resistant population termed glioblastoma stem cells (GSCs). In an effort to identify novel therapeutic targets for GBM with potential efficacy against the GSC sub-population, we queried the mRNA levels of mitotic regulators between GSCs and the neoplastic cells without stem cell characteristic, or non-GSCs. One target, the mitotic kinesin, Eg5, was consistently elevated in GSCs on both the mRNA and protein levels with increased expression correlated with higher-grade glioma and poor prognosis. Highly specific inhibitors of Eg5 are available and several have moved to phase I and II clinical trials in patients with solid malignancies. We found that GSCs exhibited a greater sensitivity to the Eg5 inhibitor ispinesib compared to non-GSCs from the same tumor and that inhibition of Eg5 compromised the key stem cell characteristics of self-renewal and tumor initiation. Using an orthotopic xenograft model, we demonstrated the first in vivo evidence for efficacy of Eg5 inhibition on glioblastoma tumor progression. An unexpected impact on invasion was observed following Eg5 inhibition resulting in the identification of a hitherto unappreciated role for Eg5 outside of cellular proliferation. We therefore propose that Eg5 inhibitors hold promise in preventing treatment resistance and recurrence in GBM and may provide a novel therapeutic target for GSCs.