Medulloblastoma (MB) is the most common malignant brain tumor in children. Although aggressive treatments have improved outcomes, many MB patients still die of their disease, and survivors suffer severe long-term side effects from the therapy. Thus, an increased understanding of the disease and improved therapeutic approaches are critical. MB is comprised of four subgroups ? WNT, Sonic hedgehog (SHH), Group 3 and Group 4 ? that differ in terms of genetics, epigenetics, clinical characteristics and outcomes. Although we have some mechanistic understanding of WNT, SHH and Group 3 tumors, the genes and pathways that underlie Group 4, the most prevalent form of the disease, remain a mystery. Identifying oncogenic drivers and using them to create animal models of Group 4 MB is critical for development and testing of new therapies. Our analysis of the genome and epigenome of >400 human Group 4 MBs has identified single nucleotide variants (SNVs) as well as chromosomal copy number alterations (CNAs). While these studies have generated lists of candidate drivers, none of these has been tested or proven necessary or sufficient to initiate tumor growth. We hypothesize that perturbing expression of candidate genes or CNAs in neural progenitors will generate models of Group 4 MB, thereby validating their functional importance. To test this hypothesis, we propose to knock out or overexpress genes in murine and human (iPS-derived) neural progenitors and evaluate tumorigenic potential in vivo. These studies will create robust models of Group 4 MB that can be used to study tumor biology and to identify novel approaches to therapy.

Public Health Relevance

These studies are focused on the understanding the mechanisms underlying medulloblastoma, the most common malignant brain tumor in children. Defining the pathways that are altered in this tumor will allow us to identify new approaches to treatment, and develop animal models that can be used to test therapies before moving them forward to the clinic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA159859-09
Application #
9863752
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Mietz, Judy
Project Start
2017-02-01
Project End
2022-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Sanford Burnham Prebys Medical Discovery Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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