DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets
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 targe...
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| Format: | Article |
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American Association for Cancer Research (AACR)
2018
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| Online Access: | http://hdl.handle.net/1721.1/117638 https://orcid.org/0000-0001-7963-402X https://orcid.org/0000-0002-3772-8156 https://orcid.org/0000-0001-9249-8181 |
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| author | Hanaford, A. R. Price, A. Kahlert, U. D. Maciaczyk, J. Nikkhah, G. Dancik, V. Seashore-Ludlow, B. Viswanathan, V. Rees, M. G. Eberhart, C. G. Raabe, E. H. Archer, Tenley Kim, Jong Wook Ehrenberger, Tobias Clemons, Paul A Stewart, Michelle L. Shamji, Alykhan Fraenkel, Ernest Pomeroy, Scott L. Tamayo, Pablo Schreiber, Stuart L. Mesirov, Jill P. |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Hanaford, A. R. Price, A. Kahlert, U. D. Maciaczyk, J. Nikkhah, G. Dancik, V. Seashore-Ludlow, B. Viswanathan, V. Rees, M. G. Eberhart, C. G. Raabe, E. H. Archer, Tenley Kim, Jong Wook Ehrenberger, Tobias Clemons, Paul A Stewart, Michelle L. Shamji, Alykhan Fraenkel, Ernest Pomeroy, Scott L. Tamayo, Pablo Schreiber, Stuart L. Mesirov, Jill P. |
| author_sort | Hanaford, A. R. |
| collection | MIT |
| description | 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 MYCdriven Group 3 medulloblastoma tumors in carefully selected patients. |
| first_indexed | 2024-09-23T13:22:08Z |
| format | Article |
| id | mit-1721.1/117638 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:22:08Z |
| publishDate | 2018 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1176382022-09-28T13:42:50Z DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets Hanaford, A. R. Price, A. Kahlert, U. D. Maciaczyk, J. Nikkhah, G. Dancik, V. Seashore-Ludlow, B. Viswanathan, V. Rees, M. G. Eberhart, C. G. Raabe, E. H. Archer, Tenley Kim, Jong Wook Ehrenberger, Tobias Clemons, Paul A Stewart, Michelle L. Shamji, Alykhan Fraenkel, Ernest Pomeroy, Scott L. Tamayo, Pablo Schreiber, Stuart L. Mesirov, Jill P. Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology. Department of Mathematics Massachusetts Institute of Technology. Department of Mechanical Engineering Koch Institute for Integrative Cancer Research at MIT Archer, Tenley Kim, Jong Wook Ehrenberger, Tobias Clemons, Paul A Stewart, Michelle L. Shamji, Alykhan Schreiber, Stuart Fraenkel, Ernest Pomeroy, Scott L. Mesirov, Jill P Tamayo, Pablo 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 MYCdriven Group 3 medulloblastoma tumors in carefully selected patients. National Institutes of Health (U.S.) (grant R01 CA154480) National Institutes of Health (U.S.) (grant R01 109467) National Institutes of Health (U.S.) (grant R01GM074024) National Cancer Institute (U.S.). Cancer Target Discovery and Development Network (U01CA176152) 2018-09-05T15:43:49Z 2018-09-05T15:43:49Z 2016-03 2016-02 2018-08-30T15:10:29Z Article http://purl.org/eprint/type/JournalArticle 1078-0432 1557-3265 http://hdl.handle.net/1721.1/117638 Hanaford, A. R., T. C. Archer, A. Price, U. D. Kahlert, J. Maciaczyk, G. Nikkhah, J. W. Kim, et al. “DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets.” Clinical Cancer Research 22, no. 15 (March 24, 2016): 3903–3914. https://orcid.org/0000-0001-7963-402X https://orcid.org/0000-0002-3772-8156 https://orcid.org/0000-0001-9249-8181 http://dx.doi.org/10.1158/1078-0432.CCR-15-3011 Clinical Cancer Research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Hanaford, A. R. Price, A. Kahlert, U. D. Maciaczyk, J. Nikkhah, G. Dancik, V. Seashore-Ludlow, B. Viswanathan, V. Rees, M. G. Eberhart, C. G. Raabe, E. H. Archer, Tenley Kim, Jong Wook Ehrenberger, Tobias Clemons, Paul A Stewart, Michelle L. Shamji, Alykhan Fraenkel, Ernest Pomeroy, Scott L. Tamayo, Pablo Schreiber, Stuart L. Mesirov, Jill P. DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets |
| title | DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets |
| title_full | DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets |
| title_fullStr | DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets |
| title_full_unstemmed | DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets |
| title_short | DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets |
| title_sort | discovering innovative therapies for rare tumors combining genetically accurate disease models with in silico analysis to identify novel therapeutic targets |
| url | http://hdl.handle.net/1721.1/117638 https://orcid.org/0000-0001-7963-402X https://orcid.org/0000-0002-3772-8156 https://orcid.org/0000-0001-9249-8181 |
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