Abstract LB-322: Casein kinase 2 is a major regulator of medulloblastoma growth

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for about 20% of all cases. While surgery, craniospinal irradiation, and chemotherapy have resulted in a cure rate of 70%, the surviving patients are afflicted with neurocognitive impairment, endocrine dysfunction, and a severe decrease in quality of life. Consequently, better and more effective treatments are needed to treat these young patients. Casein kinase 2 (CK2) is an intriguing therapeutic target for MB because it is dysregulated in all the MB molecular subgroups and patients with high CK2 expression have a significantly worse prognosis. To elucidate the role of CK2 in MB we transduced multiple MB cell lines with CK2 isoforms. We discovered that a CK2 isoform, CK2a, increased tumorigenesis in both the Sonic Hedgehog and Group 3 MB subgroups, while knocking down expression ameliorated MB growth. Through these transduced cell lines we also determined that CK2 can regulate MB tumorigenesis through b-catenin and potentially GLI1. Moreover, mice orthotopically injected with MB cells over-expressing CK2a or CK2b displayed a reduced survival compared to control. We extended our analysis to a CK2 inhibitor, CX-4945, which is currently undergoing phase I/II clinical trials for toxicity and safety. Treatment with CX-4945 reduced MB cell growth and also reduced expression of MGMT, a well-known regulator of temozolomide (TMZ) efficacy. Our findings were corroborated when we screened 4,000 FDA approved compounds to identify molecules that work synergistically with CX-4945. TMZ was one of the major compounds that were identified in the screen, suggesting that CX-4945 treatment can sensitize MB cells to TMZ by dysregulating MGMT. Combinatorial treatment with CX-4945 and TMZ had a synergistic effect on reducing MB tumor growth. Together, our findings suggest that CK2 is a novel therapeutic target for MB and that combining CX-4945 and TMZ can lead to a promising new MB therapy. Citation Format: Ryan Nitta, Sara Matilda Bolin, Ginikachi Nwagbo, Teresa Purzner, Suzana Kahn, Yoon-Jae Cho, Gordon Li. Casein kinase 2 is a major regulator of medulloblastoma growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-322.