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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA096832-09S1
Application #
8459545
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$12,250
Indirect Cost
$5,250
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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