Co-targeting CK1ɛ and PIK3CB/p110β as a Therapeutic Approach for Glioblastoma. (P11-13.005)

Abstract

<h3>Objective:</h3> To determine whether co-inhibition of CK1ɛ and PIK3CB/p110β is an effective therapeutic treatment for Glioblastoma (GBM). <h3>Background:</h3> GBM remains the most common and malignant brain cancer in adults with dismal prognosis, largely due to lack of effective treatments. CK1ɛ and PIK3CB/p110β have been identified as GBM survival kinase genes. CK1ɛ promotes growth of GBM cells by inhibiting β-catenin. However, blocking CK1ɛ alone fails to completely block tumor growth perhaps because β-catenin can be regulated by other kinases, including PIK3CB/p110β. It is possible that blocking either CK1ɛ or PIK3CB/p110β alone does not substantially activate β-catenin to induce massive GBM cell death, thus limiting their therapeutic efficacy as a single agent. It is therefore imperative to investigate if co-targeting CK1ɛ and PIK3CB/p110β yields synergistic inhibitory effects on GBM cell growth. <h3>Design/Methods:</h3> GBM cells were treated with either DMSO (control), IC261 (chemical inhibitor of CK1ɛ), GSK2636771 (chemical inhibitor of PIK3CB/p110β), or both IC261 and GSK2636771. Cell viability was measured using the MTS viability assay. <h3>Results:</h3> Cell viability for the treatment groups were as follows: GSK2636771 (95.76%), IC261 (61.84%), and combination of GSK2636771+IC261 (41.70%). Statistical analysis of drug synergy using the Bliss independence model yielded an Excess Over Bliss score greater than 0%, indicating a synergistic effect. <h3>Conclusions:</h3> Preliminary results show that co-inhibition of CK1ɛ and PIK3CB/p110β with chemical inhibitors yields synergistic GBM cell death. Future directions include a dose response experiment to determine the most effective dose of GSK2636771 and IC261 in order to yield stronger synergistic effects. To further elucidate the mechanism of GBM cell death, immunoblotting will also be performed to detect β-catenin activity after inhibition of CK1ɛ and PIK3CB/p110β. <b>Disclosure:</b> Miss Xu has nothing to disclose. Zhi Sheng, 1800 has nothing to disclose.