Over the last 10 years approximately 750 children with medulloblastoma have been treated on consortia-based clinical trials at an estimated cost of over $150 million. Despite this enormous effort, little meaningful molecular data have been generated that will inform the next generation of clinical studies. Consequently, all patients currently receive the same aggressive combination of surgery, radiation and chemotherapy. This treatment inflicts devastating side effects on survivors and fails to cure about one quarter of patients. Using gene expression microarray profiling, we have identified subgroups of human medulloblastoma that display distinct patterns of gene expression, chromosomal alteration, histology and prognosis. The sum of this research suggests that medulloblastoma comprises several subgroups that are likely to require different types or intensities of therapy;however, we still lack the comprehensive understanding of these subgroups necessary to develop new treatments. Work from our group and others has shown that subgroups of brain tumors are generated by cancer stem cells (CSC) that share the gene expression profiles of distinct neural progenitor cells, allowing the identification of their candidate cells-of-origin. Our preliminary data show that two emerging subgroups of medulloblastoma that contain activating mutations in the Sonic hedgehog pathway (from here termed SHH-subgroup) and BETA-CATENIN (CTNNB1-subgroup) display the gene expression profiles of granule neuron precursor cells (GNPC) and precursor cells within the precerebellar neuroepithelium (PCN), respectively. These data suggest the hypothesis that: distinct populations of progenitor cells within the developing hindbrain are predisposed to acquire different gene mutations that transform these into CSC. Since these CSC have distinct cellular origins and molecular properties, then they generate disease subgroups that display different biological and clinical characteristics. We will test this hypothesis by focusing on the SHH and CTNNB1-subgroups of medulloblastoma to: (i) develop the first ever spontaneous mouse model of CTNNB1-subgroup disease;(ii) Determine if SHH and CTNNB1-subgroups are generated by distinct types of CSC and associated CSC niches, (iii) Develop approved diagnostic tests of SHH and CTNNB1-subgroup tumors that can select patients with these tumors for clinical trial, and validate the prognostic significance of CTNNB1- disease in a large prospective clinical trial.

Public Health Relevance

Medulloblastoma?the most common malignant pediatric brain tumor?includes a group of heterogeneous tumors for which we have only one set of aggressive treatments. By developing a new model of an important subgroup of medulloblastoma, conducting state-of-the-art cancer stem cell assays and integrating these data with studies of tumors from a larg prospective clinical trial, we will significantly advance understanding of medulloblastoma biology, the origin of disease subgroups, and the development of new therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
St. Jude Children's Research Hospital
United States
Zip Code
Dumitrache, Lavinia C; McKinnon, Peter J (2017) Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease. Mech Ageing Dev 161:121-129
Hoch, Nicolas C; Hanzlikova, Hana; Rulten, Stuart L et al. (2017) XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541:87-91
Vo, BaoHan T; Li, Chunliang; Morgan, Marc A et al. (2017) Inactivation of Ezh2 Upregulates Gfi1 and Drives Aggressive Myc-Driven Group 3 Medulloblastoma. Cell Rep 18:2907-2917
Wei, Lei; Murphy, Brian L; Wu, Gang et al. (2017) Exome sequencing analysis of murine medulloblastoma models identifies WDR11 as a potential tumor suppressor in Group 3 tumors. Oncotarget 8:64685-64697
Illuzzi, Jennifer L; McNeill, Daniel R; Bastian, Paul et al. (2017) Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes. Environ Mol Mutagen 58:84-98
Genthe, Jamie R; Min, Jaeki; Farmer, Dana M et al. (2017) Ventromorphins: A New Class of Small Molecule Activators of the Canonical BMP Signaling Pathway. ACS Chem Biol 12:2436-2447
Pajtler, Kristian W; Mack, Stephen C; Ramaswamy, Vijay et al. (2017) The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 133:5-12
Fukuda, Yu; Wang, Yao; Lian, Shangli et al. (2017) Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesis. JCI Insight 2:
Nakanishi, Takeo; Ohno, Yasuhiro; Aotani, Rika et al. (2017) A novel role for OATP2A1/SLCO2A1 in a murine model of colon cancer. Sci Rep 7:16567
Enriquez-Rios, Vanessa; Dumitrache, Lavinia C; Downing, Susanna M et al. (2017) DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neurogenesis. J Neurosci 37:893-905

Showing the most recent 10 out of 186 publications