Molecular-targeted therapies are within reach of 21st century cancer medicine. Although medulloblastoma is the most common malignant brain tumor of childhood, the identity of molecules that are useful therapeutic targets in medulloblastoma is largely unknown due to the lack of fundamental knowledge on the molecular pathogenesis of the disease. Our long-term goal is to identify critical genes that drive the oncogenic process in medulloblastoma and to better understand their roles in the pathogenesis of medulloblastoma. The objective of this application is to determine how medulloblastoma cell growth is controlled by orthodenticle homolog-2, or OTX2, a medulloblastoma oncogene which has been shown to be amplified and/or overexpressed in medulloblastomas. Our central hypothesis is that OTX2 is essential for medulloblastoma cell proliferation and survival, and that the oncogenic effects of OTX2 are mediated through transcriptional regulation of its direct downstream target, namely the oncogene c-Myc. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: (1) to determine the oncogenic effects of OTX2 overexpression and to determine the extent and prevalence of OTX2 gene amplification;(2) to determine the effects of OTX2 inhibition on medulloblastoma cell survival and proliferation;and (3) to determine that c-Myc is a downstream target of OTX2 and responsible for OTX2-mediated oncogenic effects. Under the first aim, OTX2 genetic changes will be examined, and the oncogenic effects of OTX2 overexpression will be characterized in cell culture and in xenograft models. Under the second aim, a validated RNA interference approach will be used to inhibit expression of OTX2 to determine the role of OTX2 in medulloblastoma cell survival and proliferation. Under the third aim, a combination of functional assays, including pathway delineation, promoter assays, and gene expression studies, will be applied to investigate the role of c-Myc in OTX2-mediated oncogenic effects. Our approach to unravel the molecular mechanisms involved in medulloblastoma pathogenesis is innovative because it will focus on the role of a newly identified oncogene involved in the genesis of the disease. Relevance to Public Health: The proposed research has the potential to advance our knowledge of the pathogenesis of medulloblastoma which could make significant contributions to the therapeutic intervention in this frequently lethal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA118822-04S1
Application #
7881166
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Ogunbiyi, Peter
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2009-07-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$60,080
Indirect Cost
Name
Duke University
Department
Pathology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Wortham, Matthew; Guo, Changcun; Zhang, Monica et al. (2014) Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma. PLoS One 9:e107156
López, G Y; Grant, G A; Fuchs, H E et al. (2014) Clinico-pathological description of three paediatric medulloblastoma cases with MLL2/3 gene mutations. Neuropathol Appl Neurobiol 40:217-20
Wortham, Matthew; Yan, Hai (2012) Apples to origins: identifying brain tumor stem cell genes by comparing transcriptomes of normal and cancer stem cells. Cancer Discov 2:492-4
Wortham, Matthew; Jin, Genglin; Sun, Julia Lailai et al. (2012) Aberrant Otx2 expression enhances migration and induces ectopic proliferation of hindbrain neuronal progenitor cells. PLoS One 7:e36211
Parsons, D Williams; Li, Meng; Zhang, Xiaosong et al. (2011) The genetic landscape of the childhood cancer medulloblastoma. Science 331:435-9
McLendon, Roger E; Adekunle, Adesina; Rajaram, Veena et al. (2011) Embryonal central nervous system neoplasms arising in infants and young children: a pediatric brain tumor consortium study. Arch Pathol Lab Med 135:984-93
Lopez, Giselle Y; Reitman, Zachary J; Solomon, David et al. (2010) IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain. Biochem Biophys Res Commun 398:585-7
Adamson, David C; Shi, Qun; Wortham, Matthew et al. (2010) OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas. Cancer Res 70:181-91
Duncan, Christopher G; Killela, Patrick J; Payne, Cathy A et al. (2010) Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes. Oncotarget 1:265-77
Reitman, Zachary J; Yan, Hai (2010) Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 102:932-41

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