Medulloblastomas are the most common malignant brain tumors in children. More than one third of children with these tumors do not survive and essentially 100% of survivors have life changing neurocognitive sequelae. New approaches to treatment with reduced toxicity are needed. In the first five years of this project, the largest medulloblastoma genomic dataset created to date was established. Using integrated analysis of molecular, genomic and clinical data, medulloblastomas were discovered to consist of multiple molecular subtypes, each with a unique molecular signature reflecting underlying mechanisms of tumorigenesis and correlated with clinical outcome. These data were used to develop the most accurate risk-stratification schema developed to date, which proved to be generalizable to a fully independent dataset. The goals of the next funding period will be to define molecular subtypes at a deeper level, to identify molecular markers for targeted therapies, and to complete the development of our risk stratification model with a goal of translating to a test with that will be incorporated into the next generation of medulloblastoma clinical trials. These goals will be accomplished through the following Specific Aims: 1) Refine and validate medulloblastoma subtyping and outcome prediction in large-scale multi-institutional prospective clinical trials;2) Implement a "real time" test for risk stratification and molecular subtyping of medulloblastoma patients;and 3) Develop an interactive website, or portal, which will provide a single, web-based, publicly available gateway to deliver genomic data, genesets, and computational methodology to the general clinical and scientific community.

Public Health Relevance

The goal of this project is to understand how specific intrinsic molecules are related to the clinical behavior of medulloblastomas, the most common malignant brain tumors in children. Molecular markers will be developed to predict outcome so that conventional chemotherapy and radiation treatments can be optimized for maximal efficacy and to minimize damage to the developing brain. Molecular mechanisms will be identified to develop effective targeted therapies that may ultimately replace conventional treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109467-08
Application #
8469397
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Timmer, William C
Project Start
2004-08-01
Project End
2016-05-31
Budget Start
2013-06-28
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$694,001
Indirect Cost
$133,341
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Gottardo, Nicholas G; Hansford, Jordan R; McGlade, Jacqueline P et al. (2014) Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol 127:189-201
Sengupta, Soma; Weeraratne, Shyamal D; Cho, Yoon-Jae et al. (2014) Could ?5-GABA-A receptor activation be used as a target for managing medulloblastomas? CNS Oncol 3:245-7
Teo, Wan-Yee; Elghetany, M Tarek; Shen, Jianhe et al. (2014) Therapeutic implications of CD1d expression and tumor-infiltrating macrophages in pediatric medulloblastomas. J Neurooncol 120:293-301
Akhavanfard, Sara; Vargas, Sara O; Han, Moonjoo et al. (2014) Inactivation of the tumor suppressor WTX in a subset of pediatric tumors. Genes Chromosomes Cancer 53:67-77
Sengupta, Soma; Weeraratne, Shyamal Dilhan; Sun, Hongyu et al. (2014) *5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth. Acta Neuropathol 127:593-603
Zhu, Zehua; Aref, Amir R; Cohoon, Travis J et al. (2014) Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov 4:452-65
Shao, Diane D; Tsherniak, Aviad; Gopal, Shuba et al. (2013) ATARiS: computational quantification of gene suppression phenotypes from multisample RNAi screens. Genome Res 23:665-78
Ramkissoon, Lori A; Horowitz, Peleg M; Craig, Justin M et al. (2013) Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A 110:8188-93
Teo, Wan-Yee; Shen, Jianhe; Su, Jack Meng Fen et al. (2013) Implications of tumor location on subtypes of medulloblastoma. Pediatr Blood Cancer 60:1408-10
Weeraratne, Shyamal Dilhan; Amani, Vladimir; Teider, Natalia et al. (2012) Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma. Acta Neuropathol 123:539-52

Showing the most recent 10 out of 26 publications