Abstract 3982: Dual inhibition of HDAC and PI3 kinase signaling pathways with CUDC-907 in treatment of p53-driven medulloblastoma

Abstract

Abstract Comprehensive studies of the medulloblastoma (MB) genome, epigenome and transcriptome have placed MB in four molecular subgroups: WNT, SHH, and two non-WNT/non-SHH: Group 3 and Group 4. Furthermore, studies suggest that p53-mutated SHH MBs frequently harbor genetic anomalies involving MYCN and GLI2 amplifications, which confer poor prognosis and resistance to treatments. The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) intracellular signaling pathway that regulates cell growth, survival and invasion, is commonly deregulated in MB. Therefore, the PI3K/Akt/mTOR pathway may be a suitable target for therapeutic intervention. Moreover, Histone deacetylases (HDAC) regulate cancer initiation and progression, and studies have shown that small molecule inhibitors of HDAC can effectively limit MB proliferation. We aim to determine the status of tumor suppressor gene p53 in defining metastatic potential in SHH-MB and to establish the therapeutic efficacy of targeting these pathways in p53-driven MB cells with a dual agent or individual agents. Immunohistochemistry and FISH were used to determine the status of mutant p53 and MYC amplification or iso-p53, respectively, in MB tumors (n=41). p53-mutant MB cell line was used to investigate the signaling pathway that regulates proliferation, migration, and drug resistance using inhibitors of HDAC (LBH-589) and PI3K/mTOR (BKM-120/rapamycin) or CUDC-907 (dual inhibitor of HDACs and the PI3K/AKT). Results demonstrated that: 1) GAB-1 was highly expressed in the Shh group (82%) and KV1 expression was evenly distributed in all subtypes; 2) loss of p53 and overexpression of MYC varied in each subtype, but did not correlate with metastasis; 3) combined treatment with LBH-589 and BKM-120 or single treatment with CUDC-907 reduced cell proliferation, migration and S-phase entry; 4) MB cells were resistant to BKM -120, while LBH-589 or CUDC-907 caused apoptosis; 5) tumor formation was suppressed by BKM-120 given with mTOR inhibitors; 6) AKT and 4E-BP1 dephosphorylated following treatments with BKM-120 or CUDC-907. In conclusion, despite current clinical limitations, dual HDAC and PI3K inhibitors may benefit the understanding of aberrant signaling pathways in genetically driven MB, and may provide basis for future targeted therapies. Citation Format: Jennifer S. Ronecker, Julia Pazniokas, Anubhav G. Amin, Raphael Salles Scortegagna de Medeiros, Sidnei Epelman, Chirag Ghandi, Nelci Zanon, Meic H. Schmidt, Meena Jhanwar-Uniyal. Dual inhibition of HDAC and PI3 kinase signaling pathways with CUDC-907 in treatment of p53-driven medulloblastoma [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 3982.