Molecular characterization of OTX2 as a novel therapeutic target.

"Alex's Lemonade Stand Foundation truly understood that innovative ideas need to be translated from basic science to patients. It allows us to discover tumor markers that will be useful in clinics." - Hai Yan, MD

Initial Project Goal:
Our goal was to identify critical genes that drive the oncogenic process in medulloblastoma and to better understand their roles in the pathogenesis of medulloblastoma. Specifically, we proposed to study the role of OTX2, a developmentally regulated transcription factor in medulloblastoma development.

Findings:
Analysis of a large cohort of primary medulloblastomas revealed that the OTX2 is in the genomic region that displayed frequently copy number gain. OTX2 copy number gain was restricted to tumor subtypes that did not express a molecular signature of Wnt or Shh pathway activation. Gain of OTX2 copy number was associated with the presence of anaplastic histologic features and shorter survival in medulloblastoma patients. In support of a functional role, ectopic OTX2 expression enhanced proliferation and tumorigenicity of immortalized primary cells, whereas OTX2 knockdown in medulloblastoma cells prolonged the survival of animals bearing xenograft tumors. Mechanistic investigations revealed upregulation of MYC as a potential mechanism whereby OTX2 promotes tumor progression. Our findings define OTX2 as an important oncogenic driver in medulloblastoma

Impact on Children with Medulloblastoma and Their Families:
Medulloblastomas with OTX2 overexpression are classified into the shh-independent subgroup. OTX2 and its involved oncogenic pathway targeted therapies need to be developed to treat this specific subgroup of patients.

Next Steps:
We aim to establish OTX2 dependent tumor models to develop novel therapy.

Updated March 2012.