ArticleNature genetics2018
A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.
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Article in Nature genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 125 papers.
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125citing papers in PubMed
17.0field-weighted citation impact, top 1% of its field
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Who cites it
125 citing papers in PubMed, 222 citations in OpenAlex.
- Entinostat in patients with relapsed or refractory abdominal neuroendocrine tumors.The oncologist · 2024Trial
- Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer.Nature genetics · 2026Article
- Article
- Deep molecular profiling of lung neuroendocrine tumours and supra-carcinoids.Molecular cancer · 2026Article
- Ten quick tips for causal analysis of biomedical omics data.PLoS computational biology · 2026Article
- A forward genetic screen identifies Sirtuin1 as a driver of neuroendocrine prostate cancer.The Journal of experimental medicine · 2026Article
- Multiomic analyses delineate human neuroendocrine tumor cell states in relation to normal enteroendocrine cell ontogeny.The Journal of clinical investigation · 2026Article
- Spatial Transcriptomics Reveals Location-Specific Tumor Cell Subtypes and Signaling within Multifocal Small Intestinal Neuroendocrine Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Systematic design of combination therapy by targeting master regulators of coexisting diffuse midline glioma cell states.Nature genetics · 2026Article
- Molecular taxonomy of pancreatic neuroendocrine tumors reveals BEND2-fusions-driven transcriptional plasticity and therapeutic vulnerabilities.Cell reports. Medicine · 2026Article
- Discovery of predictive biomarkers for cancer therapy through computational approaches.Nature reviews. Clinical oncology · 2026Review
- Single-cell protein activity analysis reveals aberrant myogenesis and IGF2-PI3K pathway dependencies inScience advances · 2026Article
- A proteogenomic atlas of 1032 brain metastases identifies molecular subtypes, immune landscapes, and therapeutic vulnerabilities.Nature communications · 2026Article
- Novel HSPA8-NR4A2 rearrangement in extraskeletal myxoid chondrosarcoma: a sarcoma mimicker of neuroendocrine neoplasia.Virchows Archiv : an international journal of pathology · 2025Article
- Molecular Subtypes of Pancreatic Neuroendocrine Tumors Mutated in MEN1/DAXX/ATRX Explain Biological Variability.Endocrine pathology · 2025Article
- Article
- Systematic identification and targeting of master regulator checkpoints (MRC) governing tumor microenvironment-mediated immune evasion.Journal for immunotherapy of cancer · 2025Review
- Ras-dependent activation of BMAL2 regulates hypoxic metabolism in pancreatic cancer.bioRxiv : the preprint server for biology · 2025Article
- Small intestinal neuroendocrine tumors lack early genomic drivers, acquire DNA repair defects and harbor hallmarks of low REST expression.Scientific reports · 2025Article
- Identification and targeting of regulators of SARS-CoV-2-host interactions in the airway epithelium.Science advances · 2025Article
65 more citing papers are in PubMed but not listed here.
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Authors and funding
58 authors at 20 institutions in 9 countries.
Mariano J AlvarezDepartment of Systems Biology, Columbia University, New York, NY, USA.
Prem S SubramaniamDepartment of Systems Biology, Columbia University, New York, NY, USA.
Laura H TangMemorial Sloan Kettering Cancer Center, New York, NY, USA.
Adina GrunnDepartment of Systems Biology, Columbia University, New York, NY, USA.
Mahalaxmi AburiDepartment of Systems Biology, Columbia University, New York, NY, USA.
Gabrielle RieckhofInstitute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA.
Elena V KomissarovaDepartment of Systems Biology, Columbia University, New York, NY, USA.ORCID http://orcid.org/0000-0001-6848-0635
Elizabeth A HaganDepartment of Urology, Columbia University, New York, NY, USA.
Lisa BodeiMemorial Sloan Kettering Cancer Center, New York, NY, USA.
Paul A ClemonsBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Filemon S Dela CruzDepartment of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Deepti DhallCedars-Sinai Medical Center, Los Angeles, CA, USA.
Daniel DiolaitiDepartment of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Douglas A FrakerPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Afshin GhavamiPsychoGenics Inc., Tarrytown, NY, USA.ORCID http://orcid.org/0000-0002-4222-8877
Daniel KaemmererDepartment of General and Visceral Surgery, Zentralklinik, Bad Berka, Germany.
Charles KaranSulzberger Columbia Genome Center, Columbia University, New York, NY, USA.
Mark KiddWren Laboratories, Branford, CT, USA.
Kyoung M KimDivision of Hematology Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Hee C KimDivision of Hematology Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.ORCID http://orcid.org/0000-0002-1162-9205
Lakshmi P KunjuMichigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Ülo LangelDepartment of Neurochemistry, the Arrhenius Laboratories for Nat. Sci., Stockholm University, Stockholm, Sweden.
Zhong LiFalconwood Foundation, New York, NY, USA.
Jeeyun LeeDivision of Hematology Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.ORCID http://orcid.org/0000-0002-4911-6165
Hai LiSulzberger Columbia Genome Center, Columbia University, New York, NY, USA.
Virginia LiVolsiPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Roswitha PfragnerInstitute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
Allison R RaineyDepartment of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ronald B RealubitSulzberger Columbia Genome Center, Columbia University, New York, NY, USA.
Helen RemottiDepartment of Pathology, Columbia University, New York, NY, USA.
Jakob RegbergDepartment of Neurochemistry, the Arrhenius Laboratories for Nat. Sci., Stockholm University, Stockholm, Sweden.
Robert RosesPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Anil RustgiPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Antonia R SepulvedaDepartment of Pathology, Columbia University, New York, NY, USA.
Stefano SerraDepartment of Pathology, University Health Network, University of Toronto, Toronto, Canada.
Chanjuan ShiDepartment of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
Xiaopu YuanCedars-Sinai Medical Center, Los Angeles, CA, USA.
Massimo BarberisDivision of Pathology, European Institute of Oncology, Milan, Italy.
Roberto BergamaschiDivision of Colon and Rectal Surgery, State University of New York, Stony Brook, NY, USA.
Arul M ChinnaiyanMichigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-9282-3415
Tony DetreFalconwood Foundation, New York, NY, USA.
Shereen EzzatDepartment of Pathology, University Health Network, University of Toronto, Toronto, Canada.
Andrea FrillingImperial College London, London, UK.
Merten HommannDepartment of General and Visceral Surgery, Zentralklinik, Bad Berka, Germany.
Dirk JaegerMedical Oncology, National Center for Tumor Diseases Heidelberg, University Medical Center Heidelberg, Heidelberg, Germany.
Michelle K KimMount Sinai School of Medicine, New York, NY, USA.
Beatrice S KnudsenCedars-Sinai Medical Center, Los Angeles, CA, USA.
Andrew L KungDepartment of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Emer LeahyPsychoGenics Inc., Tarrytown, NY, USA.
David C MetzPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jeffrey W MilsomDepartment of Surgery, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA.
Young S ParkDivision of Hematology Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Diane Reidy-LagunesMemorial Sloan Kettering Cancer Center, New York, NY, USA.
Stuart SchreiberBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Kay WashingtonDepartment of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
Bertram WiedenmannDepartment of Internal Medicine, Division of Gastroenterology, Charite, Universitätsmedizin Berlin, Berlin, Germany.
Irvin ModlinEmeritus Professor Gastrointestinal Surgery, School of Medicine, Yale University, New Haven, Connecticut, USA. imodlin@irvinmodlin.com.
Andrea CalifanoDepartment of Systems Biology, Columbia University, New York, NY, USA. califano@cumc.columbia.edu.
Columbia University · USMemorial Sloan Kettering Cancer Center · USUniversity of Pennsylvania · USSamsung Medical Center · KRCedars-Sinai Medical Center · USBroad Institute · USPsychogenics (United States) · USStockholm University · SEUniversity Health Network · CAVanderbilt University Medical Center · USZentralklinik Bad Berka · DECharité - Universitätsmedizin Berlin · DEColumbia University Irving Medical Center · USDarwinHealth (United States) · USEuropean Institute of Oncology · ITHeidelberg University · DEHoward Hughes Medical Institute · USIcahn School of Medicine at Mount Sinai · USImperial College London · GBMedical University of Graz · AT
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MUnderstanding and Controlling p120 Dysfunction in CRCP50CA095103 · NCI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI COFFEY, ROBERT J. · 2002 to 2017
$33.6MPredicting Cancer Cell Response to Endogenous and Exogenous Perturbations at the Single Cell LevelR35CA197745 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI ANDREA CALIFANO · 2015 to 2026
$11.5MSystematic pharmacological targeting of the core mechanisms responsible for maintaining cancer cell stateU54CA209997 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CALIFANO, ANDREA, HONIG, BARRY H · 2016 to 2021
$10.9MCedars-Sinai Biobank and Translational Research Core Facility (CS-BRCF)G20RR030860 · NCRR · CEDARS-SINAI MEDICAL CENTER · PI MELMED, SHLOMO · 2010 to 2010
$9.6MSystematic Identification and Pharmacological Targeting of Tumor Dependencies for Precision Cancer MedicineU01CA217858 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CALIFANO, ANDREA · 2017 to 2021
$6.1MHigh-performance compute cluster for biomedical computingS10OD012351 · OD · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CALIFANO, ANDREA · 2012 to 2012
$2.0MStorage System for High Performance ComputingS10OD021764 · OD · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CALIFANO, ANDREA · 2016 to 2016
$600kNCI NIH HHS P30 CA008748NCI NIH HHS P50 CA095103NCI NIH HHS R35 CA197745NCI NIH HHS U01 CA217858NCI NIH HHS U54 CA209997NCRR NIH HHS G20 RR030860NIH HHS S10 OD012351NIH HHS S10 OD021764
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.
Indexed as
Antineoplastic AgentsBenzamidesCell Line, TumorCohort StudiesGastrointestinal TractHistone Deacetylase InhibitorsHistone DeacetylasesHumansIntestinal NeoplasmsNeuroendocrine TumorsPancreasPancreatic NeoplasmsPrecision MedicinePyridinesStomach NeoplasmsAntineoplastic AgentsBenzamidesentinostatHistone Deacetylase InhibitorsHistone DeacetylasesPyridines
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