CSIG-01. CASEIN KINASE 2 IS A MAJOR REGULATOR OF MEDULLOBLASTOMA GROWTH AND METASTASIS

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. 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 a highly conserved pleiotropic serine/threonine kinase that has been associated with cell survival in many cancers including adult brain tumors. CK2 is an intriguing therapeutic target for solid tumors and a phase I/II clinical trial testing the safety and tolerability of the CK2 inhibitor CX-4945 is now underway. Our findings demonstrate that CK2 plays an integral role in MB tumorigenesis and metastasis. We have discovered that the CK2 isoform, CK2a, has increased expression in all MB molecular subgroups. Also MB patients with elevated CK2a expression have a significantly worse prognosis. To determine if CK2 plays an important role in MB tumorigenesis we generated MB cell lines with modulated CK2 isoform (CK2a or CK2b) expression. We discovered that exogenous expression of CK2a, increased MB cell growth ∼3-fold, while CK2b expression increased growth ∼2-fold. Consistently, treatment with different CK2 inhibitors (CX-4945, TBB, TBBz) decreased MB cell growth 2- to 3-fold. We expanded our analysis to MB metastasis and discovered that CK2 can regulate MB cell migration and invasion. Lastly, we screened 4,000 FDA approved compounds to identify molecules that work synergistically with CX-4945 to reduce MB cell growth. We discovered that temozolomide (TMZ), which is part of the standard of care for adult brain tumors, reduced MB growth an additional 40% over CX-4945 treatment alone. Our data suggests that CK2 regulates MB tumorigenesis and metastasis, and inhibition of CK2 with CX-4945 is a promising new MB therapeutic.