Abstract IA21: Pediatric medulloblastoma: Drug screens and preclinical studies
2015
Medulloblastoma (MB) is the most common malignant brain tumor that develops in the cerebellum. MB occurs mostly in children between the ages of 3-7 years. Human MBs are classified into four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which with distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs represent the most aggressive subgroups and the least curable with current therapeutic regimen. Whole genome sequencing and gene expression analysis of human G3 MBs demonstrated C-MYC (MYC) overexpression, from gene amplification in ~17% of cases, stem like properties and high levels of EZH2 and histone 3 lysine 27 trimethylation (H3K27me3) marks. G3 MBs have few, recurrent oncogenic point mutations that might be targeted therapeutically but contain large chromosomal copy number changes and an aberrant epigenome. We developed a mouse model of G3 MB using orthotopic transplantation as well as in utero electroporation approaches by enforcing the expression of Myc with loss of p53 function that shares many characteristics of its human counterpart including high levels of Ezh2 and H3K27me3 marks. A high throughput screen of FDA-approved drugs on mouse G3 MB neuropsheres identified Pemetrexed and Gemcitabine that, in combination with standard of care chemotherapy, greatly increased the survival of mice bearing mouse or human G3 MBs. Because genetic alterations found in human G3 MBs occur in epigenetic regulators, we tested several drugs that target the epigenome to re-establish normal gene expression profiles, including those of tumor suppressor genes. Using a preclinical drug development pipeline, we evaluated nine compounds that are believed to modulate the epigenome. Of the nine compounds tested we found that the nucleoside analog 5-fluoro-2′-deoxycytidine (FdCyd) markedly reduced the proliferation of G3 MBs in vitro at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in the tECF (tumor extra cellular fluid) necessary to inhibit tumor cell proliferation in vivo. However, despite promising in vitro activity and in vivo PK properties, FdCyd was completely ineffective in treating mouse and human G3 MBs in vivo. Our studies highlight the requirement for a comprehensive and integrated preclinical drug development pipeline with mouse and human medulloblastoma to identify the best candidate drug to be translated into the clinic and to avoid taking a drug forward that looks feasible in in vitro screens but which efficacy does not translate into an in vivo setting. Citation Format: Marie Morfouace, Yogesh Patel, Anang Shelat, Daisuke Kawauchi, Giles W. Robinson, Kip Guy, Richard J. Gilbertson, Clinton Stewart, Amar Gajjar, Martine F. Roussel. Pediatric medulloblastoma: Drug screens and preclinical studies. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA21.
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