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

Publication ,  Journal Article
Alvarez, MJ; Subramaniam, PS; Tang, LH; Grunn, A; Aburi, M; Rieckhof, G; Komissarova, EV; Hagan, EA; Bodei, L; Clemons, PA; Dela Cruz, FS ...
Published in: Nat Genet
July 2018

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.

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Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

July 2018

Volume

50

Issue

7

Start / End Page

979 / 989

Location

United States

Related Subject Headings

  • Stomach Neoplasms
  • Pyridines
  • Precision Medicine
  • Pancreatic Neoplasms
  • Pancreas
  • Neuroendocrine Tumors
  • Intestinal Neoplasms
  • Humans
  • Histone Deacetylases
  • Histone Deacetylase Inhibitors
 

Citation

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Alvarez, M. J., Subramaniam, P. S., Tang, L. H., Grunn, A., Aburi, M., Rieckhof, G., … Califano, A. (2018). A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors. Nat Genet, 50(7), 979–989. https://doi.org/10.1038/s41588-018-0138-4
Alvarez, Mariano J., Prem S. Subramaniam, Laura H. Tang, Adina Grunn, Mahalaxmi Aburi, Gabrielle Rieckhof, Elena V. Komissarova, et al. “A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.Nat Genet 50, no. 7 (July 2018): 979–89. https://doi.org/10.1038/s41588-018-0138-4.
Alvarez MJ, Subramaniam PS, Tang LH, Grunn A, Aburi M, Rieckhof G, et al. A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors. Nat Genet. 2018 Jul;50(7):979–89.
Alvarez, Mariano J., et al. “A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.Nat Genet, vol. 50, no. 7, July 2018, pp. 979–89. Pubmed, doi:10.1038/s41588-018-0138-4.
Alvarez MJ, Subramaniam PS, Tang LH, Grunn A, Aburi M, Rieckhof G, Komissarova EV, Hagan EA, Bodei L, Clemons PA, Dela Cruz FS, Dhall D, Diolaiti D, Fraker DA, Ghavami A, Kaemmerer D, Karan C, Kidd M, Kim KM, Kim HC, Kunju LP, Langel Ü, Li Z, Lee J, Li H, LiVolsi V, Pfragner R, Rainey AR, Realubit RB, Remotti H, Regberg J, Roses R, Rustgi A, Sepulveda AR, Serra S, Shi C, Yuan X, Barberis M, Bergamaschi R, Chinnaiyan AM, Detre T, Ezzat S, Frilling A, Hommann M, Jaeger D, Kim MK, Knudsen BS, Kung AL, Leahy E, Metz DC, Milsom JW, Park YS, Reidy-Lagunes D, Schreiber S, Washington K, Wiedenmann B, Modlin I, Califano A. A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors. Nat Genet. 2018 Jul;50(7):979–989.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

July 2018

Volume

50

Issue

7

Start / End Page

979 / 989

Location

United States

Related Subject Headings

  • Stomach Neoplasms
  • Pyridines
  • Precision Medicine
  • Pancreatic Neoplasms
  • Pancreas
  • Neuroendocrine Tumors
  • Intestinal Neoplasms
  • Humans
  • Histone Deacetylases
  • Histone Deacetylase Inhibitors