? Project 3 Medulloblastoma (MB) is a tumor of the hindbrain that occurs in children with a peak incidence between the ages of 3 and 7, although it can occur rarely in adults. Based on accumulating molecular evidence, medulloblastoma is now classified into four major subgroups. Two subgroups are characterized by constitutive activation of developmental pathways, Sonic Hedgehog (SHH) and Wingless (WNT). Group 3 (G3), in which C-MYC (MYC) is over-expressed, and Group 4 (G4), are less well characterized and carry the worse prognosis. During the last funding cycle, in collaboration with our P01 colleagues, we developed a mouse model that mimicked the histological and molecular features of human G3 MB. This mouse model allowed the identification of two FDA-approved drugs by high-throughput screening, that increased survival of mice bearing either mouse of human G3 MBs, when used alone or in combination. Recent genome-wide sequencing of MBs showed that mutations in enzymes that modify histone H3 are among the most common abnormalities in MB. In G3 MB, loss of function mutations of the histone H3 lysine 27 (H3K27) de-methylase KDM6A or mutually exclusive patterns of overexpression of the H3K27 methylase EZH2 drive elevated levels of histone H3 lysine 27 trimethylation. We will use our mouse model and patient- derived xenografts of G3 medulloblastoma to investigate the role of histone H3 modification in G3 MB, including specific evaluation of the contribution of EZH2 and KDM6A to G3 MB development and the epigenetic signature of G3 MBs. We will screen libraries of well-annotated and validated compounds targeting epigenetic modifers that will be assessed in mouse and human G3 tumor-bearing animals as single agents or in combination with current therapeutic regimens. These studies will provide new insights into the connections between MYC, epigenetics, neural development and MB tumorigenesis.

Public Health Relevance

Medulloblastoma is the most common malignant brain tumor in children. Of the four subgroups, Group3 is the most aggressive and patients invariably experience recurrence with metastases and die of their disease. The development of a mouse model and patient-derived xenografts of Group 3 medulloblastoma may lead to a better understanding of the mutations that drive Group 3 tumorigenesis and may lead to the identification of novel targets for therapeutic intervention to improve survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
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St. Jude Children's Research Hospital
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Pajtler, Kristian W; Wen, Ji; Sill, Martin et al. (2018) Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol 136:211-226
Teitz, Tal; Fang, Jie; Goktug, Asli N et al. (2018) CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. J Exp Med 215:1187-1203
Tsang, Derek S; Burghen, Elizabeth; Klimo Jr., Paul et al. (2018) Outcomes After Reirradiation for Recurrent Pediatric Intracranial Ependymoma. Int J Radiat Oncol Biol Phys 100:507-515
Shadrick, William R; Slavish, Peter J; Chai, Sergio C et al. (2018) Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors. Bioorg Med Chem 26:25-36
Roussel, Martine F; Stripay, Jennifer L (2018) Epigenetic Drivers in Pediatric Medulloblastoma. Cerebellum 17:28-36
Waszak, Sebastian M; Northcott, Paul A; Buchhalter, Ivo et al. (2018) Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 19:785-798
El Nagar, Salsabiel; Zindy, Frederique; Moens, Charlotte et al. (2018) A new genetically engineered mouse model of choroid plexus carcinoma. Biochem Biophys Res Commun 496:568-574
Nimmervoll, Birgit V; Boulos, Nidal; Bianski, Brandon et al. (2018) Establishing a Preclinical Multidisciplinary Board for Brain Tumors. Clin Cancer Res 24:1654-1666
Vo, BaoHan T; Kwon, Jin Ah; Li, Chunliang et al. (2018) Mouse medulloblastoma driven by CRISPR activation of cellular Myc. Sci Rep 8:8733
Drosos, Yiannis; Escobar, David; Chiang, Ming-Yi et al. (2017) ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer. Sci Rep 7:11144

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