Using human neural stem cells to model brain tumors

ABSTRACT

JHU researchers developed a new method to generate genetically accurate models of rare tumors, and a companion computational methodology to find therapeutic interventions that target them. They validated their human neural stem cell model of MYC-driven Group 3 medulloblastoma and showed that CDK4/6 inhibitors are active against this subgroup. Their results suggest that palbociclib is a potential effective treatment for poor-prognosis MYC-driven Group 3 medulloblastoma tumors in carefully selected patients.

 TECHNICAL DESCRIPTION

JHU researchers used human stem and progenitor cells to develop a genetically accurate novel model of MYC-driven Group 3 medulloblastoma. They also developed a new informatics method, Disease-model Signature vs. Compound-Variety Enriched Response (“DiSCoVER”), to identify novel therapeutics that target this specific disease subtype.

Human neural stem and progenitor cells derived from the cerebellar anlage were transduced with oncogenic elements associated with aggressive medulloblastoma. An in silico analysis method for screening drug sensitivity databases (DiSCoVER) was used in multiple drug sensitivity datasets. They validated the top hits from this analysis in vitro and in vivo.

MAJOR RESULTS

1. Human neural stem and progenitor cells transformed with c-MYC, dominant-negative p53, constitutively active AKT and hTERT formed tumors in mice that recapitulated Group 3 medulloblastoma in terms of pathology and expression profile.

2. DiSCoVER analysis predicted that the aggressive MYC-driven Group 3 medulloblastoma would be sensitive to CDK inhibitors.

3. The CKD4/6 inhibitor palbociclib decreased proliferation, increased apoptosis and significantly extended the survival of mice with orthotopic medulloblastoma orthotopic xenografts.

DISEASE INDICATION
Brain Cancer

ASSOCIATED INVENTORS
Pediatric Oncology, School of Medicine
PI:  Eric Raabe, M.D., Ph.D.
Allison R Hanaford, Charles George Eberhart, M.D., Ph.D., Ulf D Kahlert, Ph.D., Jarek Maciaczyk, Ph.D., Guido Nikkhah, Ph.D.
 
ASSOCIATED PUBLICATIONS
■ Clin Cancer Res. 2016 Aug 1;22(15):3903-14 ■


 

TECHNOLOGY CLASSIFICATION

Primary Category: In Vivo Research Tool

Primary Subcategory: Discovery/Research Tools

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