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Nat Genet. 2018 Jul;50(7):979-989. doi: 10.1038/s41588-018-0138-4. Epub 2018 Jun 18.

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

Author information

1
Department of Systems Biology, Columbia University, New York, NY, USA.
2
DarwinHealth Inc, New York, NY, USA.
3
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA.
5
Department of Urology, Columbia University, New York, NY, USA.
6
Division of Pathology, European Institute of Oncology, Milan, Italy.
7
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
8
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9
Cedars-Sinai Medical Center, Los Angeles, CA, USA.
10
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
11
PsychoGenics Inc., Tarrytown, NY, USA.
12
Department of General and Visceral Surgery, Zentralklinik, Bad Berka, Germany.
13
Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA.
14
Wren Laboratories, Branford, CT, USA.
15
Division of Hematology Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
16
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
17
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
18
Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
19
Department of Neurochemistry, the Arrhenius Laboratories for Nat. Sci., Stockholm University, Stockholm, Sweden.
20
Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Tartu, Estonia.
21
Falconwood Foundation, New York, NY, USA.
22
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
23
Department of Pathology, Columbia University, New York, NY, USA.
24
Department of Pathology, University Health Network, University of Toronto, Toronto, Canada.
25
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
26
Division of Colon and Rectal Surgery, State University of New York, Stony Brook, NY, USA.
27
Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA.
28
Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
29
Imperial College London, London, UK.
30
Medical Oncology, National Center for Tumor Diseases Heidelberg, University Medical Center Heidelberg, Heidelberg, Germany.
31
Mount Sinai School of Medicine, New York, NY, USA.
32
Department of Surgery, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA.
33
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
34
Department of Internal Medicine, Division of Gastroenterology, Charite, Universitätsmedizin Berlin, Berlin, Germany.
35
Emeritus Professor Gastrointestinal Surgery, School of Medicine, Yale University, New Haven, Connecticut, USA. imodlin@irvinmodlin.com.
36
Department of Systems Biology, Columbia University, New York, NY, USA. califano@cumc.columbia.edu.
37
Department of Biomedical Informatics, Columbia University, New York, NY, USA. califano@cumc.columbia.edu.
38
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. califano@cumc.columbia.edu.
39
J.P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA. califano@cumc.columbia.edu.
40
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. califano@cumc.columbia.edu.

Abstract

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.

PMID:
29915428
PMCID:
PMC6421579
DOI:
10.1038/s41588-018-0138-4
[Indexed for MEDLINE]
Free PMC Article

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