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Ref Type Journal Article
PMID (27012813)
Authors Hanaford AR, Archer TC, Price A, Kahlert UD, Maciaczyk J, Nikkhah G, Kim JW, Ehrenberger T, Clemons PA, Dančík V, Seashore-Ludlow B, Viswanathan V, Stewart ML, Rees MG, Shamji A, Schreiber S, Fraenkel E, Pomeroy SL, Mesirov JP, Tamayo P, Eberhart CG, Raabe EH
Title DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 15
Date 2016 Aug 01
URL
Abstract Text 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.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 vivoHuman 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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CGP-082996 CGP-082996 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CGP-082996 CDK4 Inhibitor 14 CGP-082996 is an inhibitor of CDK4, which may induce cell cycle arrest and tumor cell death (PMID: 27012813).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RB1 positive medulloblastoma sensitive Palbociclib Preclinical - Pdx Actionable In a preclinical study, Ibrance (palbociclib) inhibited Rb1 phosphorylation in tumor tissues and improved survival in patient-derived intracranial xenograft models of medulloblastoma (PMID: 27012813). 27012813