Medulloblastoma is the most common malignant pediatric brain tumor. Current treatments for this disease include surgery, cranio-spinal radiation and chemotherapy. While this treatment regimen has improved survival rates, survivors face a high risk of recurrence and significant long-term quality of life issues such as uncoordinated movement, learning disabilities and social dysfunction. These side effects result from a failure of the current treatment approaches to target the tumor cells and spare the developing normal brain of young patients. Thus, a more targeted approach to treatment is necessary. However, this requires the identification of disease-specific molecular features. A subset of medulloblastomas is thought to arise from developmental defects in proliferation and neuronal differentiation of the cerebellar granule progenitor cells. The RE1 Silencing Transcription Factor (REST) is a repressor of neurogenesis. REST expression is aberrantly elevated in human medulloblastomas. This abnormal expression of REST is associated with poor prognostic significance for patients with tumors of al histological subtypes. Previous studies have shown patients with anaplastic and desmoplastic histology to have the worst and best outcomes respectively, while patients with classic histology have intermediate outcome. Unexpectedly, patients with desmoplastic tumors that exhibited REST expression have the worst outcome. These findings suggest that REST expression may contribute to tumor progression and cause a more aggressive tumor phenotype. In mice, injection of Myc-immortalized granule cell progenitors constitutively expressing REST transgene promoted tumor formation in the cerebellum. However, neither REST nor Myc alone was sufficient for tumor formation in our studies. These findings also indicate that REST may contribute to tumor progression. Interestingly, REST expression caused genetic instability, raising the possibility that REST may have a role in tumor initiation. REST knockdown in human medulloblastoma cell lines abrogated tumor formation in murine xenograft models, suggesting that REST is required for tumor maintenance. Nevertheless, a careful assessment of the temporal requirement for REST in the tumorigenic process has been hampered by the lack of appropriate mouse models. An important goal of this application is to develop a novel genetically altered mouse model in which REST expression can be conditionally elevated in the granule progenitor cells to determine if it contributes to tumor initiating events such as hyperproliferation, genetic instability and failure of neuronal differentiation. The contribution of REST to disease progression in desmoplastic tumors will also be evaluated in mouse orthotopic models. This work will provide a better understanding of REST biology in tumors and pave the way for development of REST as a novel therapeutic target for medulloblastoma.

Public Health Relevance

Medulloblastoma is the most common malignant pediatric brain tumor. Current treatments have improved survival;however patients continue to suffer poor quality of life quality. A better understanding of disease biology, a goal of the current application, will provide much needed identification of novel therapeutic targets for personalized medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Research Grants (R03)
Project #
5R03NS077021-02
Application #
8329602
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Fountain, Jane W
Project Start
2011-09-15
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$79,000
Indirect Cost
$29,000
Name
University of Texas MD Anderson Cancer Center
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Das, C M; Taylor, P; Gireud, M et al. (2013) The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation. Oncogene 32:1691-701