A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors

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MARC

Alvarez, Mariano J. (author)

A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors

Article/chapterEnglish2018

Publisher, publication year, extent ...

2018-06-18
Springer Science and Business Media LLC,2018
printrdacarrier

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LIBRIS-ID:oai:DiVA.org:su-158352
https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-158352URI
https://doi.org/10.1038/s41588-018-0138-4DOI

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Language:English
Summary in:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

Subject headings and genre

NATURVETENSKAP Biologi hsv//swe
NATURAL SCIENCES Biological Sciences hsv//eng

Added entries (persons, corporate bodies, meetings, titles ...)

Subramaniam, Prem S. (author)
Tang, Laura H. (author)
Grunn, Adina (author)
Aburi, Mahalaxmi (author)
Rieckhof, Gabrielle (author)
Komissarova, Elena V. (author)
Hagan, Elizabeth A. (author)
Bodei, Lisa (author)
Clemons, Paul A. (author)
Dela Cruz, Filemon S. (author)
Dhall, Deepti (author)
Diolaiti, Daniel (author)
Fraker, Douglas A. (author)
Ghavami, Afshin (author)
Kaemmerer, Daniel (author)
Karan, Charles (author)
Kidd, Mark (author)
Kim, Kyoung M. (author)
Kim, Hee C. (author)
Kunju, Lakshmi P. (author)
Langel, ÜloStockholms universitet,Institutionen för neurokemi,University of Tartu, Estonia(Swepub:su)ulo (author)
Li, Zhong (author)
Lee, Jeeyun (author)
Li, Hai (author)
LiVolsi, Virginia (author)
Pfragner, Roswitha (author)
Rainey, Allison R. (author)
Realubit, Ronald B. (author)
Remotti, Helen (author)
Regberg, JakobStockholms universitet,Institutionen för neurokemi (author)
Roses, Robert (author)
Rustgi, Anil (author)
Sepulveda, Antonia R. (author)
Serra, Stefano (author)
Shi, Chanjuan (author)
Yuan, Xiaopu (author)
Barberis, Massimo (author)
Bergamaschi, Roberto (author)
Chinnaiyan, Arul M. (author)
Detre, Tony (author)
Ezzat, Shereen (author)
Frilling, Andrea (author)
Hommann, Merten (author)
Jaeger, Dirk (author)
Kim, Michelle K. (author)
Knudsen, Beatrice S. (author)
Kung, Andrew L. (author)
Leahy, Emer (author)
Metz, David C. (author)
Milsom, Jeffrey W. (author)
Park, Young S. (author)
Reidy-Lagunes, Diane (author)
Schreiber, Stuart (author)
Washington, Kay (author)
Wiedenmann, Bertram (author)
Modlin, Irvin (author)
Califano, Andrea (author)
Stockholms universitetInstitutionen för neurokemi (creator_code:org_t)

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In:Nature Genetics: Springer Science and Business Media LLC50:7, s. 979-9891061-40361546-1718

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By the author/editor: Alvarez, Mariano ...; Subramaniam, Pre ...; Tang, Laura H.; Grunn, Adina; Aburi, Mahalaxmi; Rieckhof, Gabrie ...; show more...; Komissarova, Ele ...; Hagan, Elizabeth ...; Bodei, Lisa; Clemons, Paul A.; Dela Cruz, Filem ...; Dhall, Deepti; Diolaiti, Daniel; Fraker, Douglas ...; Ghavami, Afshin; Kaemmerer, Danie ...; Karan, Charles; Kidd, Mark; Kim, Kyoung M.; Kim, Hee C.; Kunju, Lakshmi P ...; Langel, Ülo; Li, Zhong; Lee, Jeeyun; Li, Hai; LiVolsi, Virgini ...; Pfragner, Roswit ...; Rainey, Allison ...; Realubit, Ronald ...; Remotti, Helen; Regberg, Jakob; Roses, Robert; Rustgi, Anil; Sepulveda, Anton ...; Serra, Stefano; Shi, Chanjuan; Yuan, Xiaopu; Barberis, Massim ...; Bergamaschi, Rob ...; Chinnaiyan, Arul ...; Detre, Tony; Ezzat, Shereen; Frilling, Andrea; Hommann, Merten; Jaeger, Dirk; Kim, Michelle K.; Knudsen, Beatric ...; Kung, Andrew L.; Leahy, Emer; Metz, David C.; Milsom, Jeffrey ...; Park, Young S.; Reidy-Lagunes, D ...; Schreiber, Stuar ...; Washington, Kay; Wiedenmann, Bert ...; Modlin, Irvin; Califano, Andrea; show less...

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NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...

Articles in the publication: Nature Genetics

By the university: Stockholm University

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