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Supplementary Figure 1 from DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets

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posted on 2023-03-31, 19:33 authored by Allison R. Hanaford, Tenley C. Archer, Antoinette Price, Ulf D. Kahlert, Jarek Maciaczyk, Guido Nikkhah, Jong Wook Kim, Tobias Ehrenberger, Paul A. Clemons, Vlado Dančík, Brinton Seashore-Ludlow, Vasanthi Viswanathan, Michelle L. Stewart, Matthew G. Rees, Alykhan Shamji, Stuart Schreiber, Ernest Fraenkel, Scott L. Pomeroy, Jill P. Mesirov, Pablo Tamayo, Charles G. Eberhart, Eric H. Raabe

Detailed diagram of the workflow of the DiSCoVER work flow

Funding

St. Baldrick's Foundation

Hyundai Hope On Wheels

Giant Food Pediatric Cancer Research

The Deming Family

Spencer Grace Foundation

Children's Brain Tumor Foundation

Johns Hopkins

NIH

Comprehensive Cancer Center Freiburg

NCI

History

ARTICLE ABSTRACT

Purpose: We used human stem and progenitor cells to develop a genetically accurate novel model of MYC-driven Group 3 medulloblastoma. We also developed a new informatics method, Disease-model Signature versus Compound-Variety Enriched Response (“DiSCoVER”), to identify novel therapeutics that target this specific disease subtype.Experimental Design: 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. We validated the top hits from this analysis in vitro and in vivo.Results: 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. DiSCoVER analysis predicted that aggressive MYC-driven Group 3 medulloblastoma would be sensitive to cyclin-dependent kinase (CDK) inhibitors. The CDK 4/6 inhibitor palbociclib decreased proliferation, increased apoptosis, and significantly extended the survival of mice with orthotopic medulloblastoma xenografts.Conclusions: We present a new method to generate genetically accurate models of rare tumors, and a companion computational methodology to find therapeutic interventions that target them. We validated our human neural stem cell model of MYC-driven Group 3 medulloblastoma and showed that CDK 4/6 inhibitors are active against this subgroup. Our results suggest that palbociclib is a potential effective treatment for poor prognosis MYC-driven Group 3 medulloblastoma tumors in carefully selected patients. Clin Cancer Res; 22(15); 3903–14. ©2016 AACR.