Abstract 302: A novel epigenetic pathway in medulloblastoma

Abstract Medulloblastoma is the most common malignant pediatric brain tumor with variable prognosis due to its clinical and genomic heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from this disease. Therefore there is a need to develop novel therapies for patients. We recently reported that Casein kinase 1δ (CK1δ) may be an attractive therapeutic target for medulloblastoma. CK1δ is a serine/threonine kinase that controls cell cycle progression, signal transduction and neurogenesis. We found high levels of CK1δ protein in mouse models of medulloblastoma and human medulloblastoma samples. Furthermore, CK1δ inhibition dramatically reduced medulloblastoma tumor progression. We demonstrate here that CK1δ phosphorylates the epigenetic reader bromodomain-containing protein 4 (BRD4). BRD4 has been identified as a therapeutic target in several cancers, including medulloblastoma. We demonstrate that CK1δ phosphorylates BRD4 and that CK1δ is required for BRD4 binding to the Gli1 promoter in vitro and in vivo. Furthermore, combined CK1δ/BRD4 inhibition is a novel means of reducing medulloblastoma growth downstream of SUFU and SMO. These studies define a novel therapeutic means of inhibiting SMO inhibitor resistant medulloblastoma. Citation Format: Nagi Ayad, Clara Penas. A novel epigenetic pathway in medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 302. doi:10.1158/1538-7445.AM2017-302