A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors
Open accessAbstract
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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Entinostat is a potent inhibitor of regulatory activities responsible for immune-evasion and metastatic potential in GEP-NET patients.
“Entinostat was also identified as a potent inhibitor of regulatory activities responsible for immune-evasion and metastatic potential in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Alvarez et al., 2018
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- Authors
- Alvarez, M. J., Subramaniam, P. S., Tang, L. H., Grunn, A., Aburi, M., Rieckhof, G., Komissarova, E. V., Hagan, E. A., Bodei, L., Clemons, P. A., Dela Cruz, F. S., Dhall, D., Diolaiti, D., Fraker, D. A., Ghavami, A., Kaemmerer, D., Karan, C., Kidd, M., Kim, K. M., Kim, H. C., Kunju, L. P., Langel, Ü., Li, Z., Lee, J., Li, H., LiVolsi, V., Pfragner, R., Rainey, A. R., Realubit, R. B., Remotti, H., Regberg, J., Roses, R., Rustgi, A., Sepulveda, A. R., Serra, S., Shi, C., Yuan, X., Barberis, M., Bergamaschi, R., Chinnaiyan, A. M., Detre, T., Ezzat, S., Frilling, A., Hommann, M., Jaeger, D., Kim, M. K., Knudsen, B. S., Kung, A. L., Leahy, E., Metz, D. C., Milsom, J. W., Park, Y. S., Reidy-Lagunes, D., Schreiber, S., Washington, K., Wiedenmann, B., Modlin, I., & Califano, A.
- Affiliations
- DarwinHealth (United States) (US)
- Columbia University (US)
- Memorial Sloan Kettering Cancer Center (US)
- NYU Langone Health (US)
- Broad Institute (US)
- Cedars-Sinai Medical Center (US)
- University of Pennsylvania (US)
- Psychogenics (United States) (US)
- Zentralklinik Bad Berka (DE)
- Wren Laboratories (United States) (US)
- Samsung Medical Center (KR)
- University of Michigan (US)
- Stockholm University (SE)
- Medical University of Graz (AT)
- University Health Network (CA)
- Vanderbilt University Medical Center (US)
- European Institute of Oncology (IT)
- Stony Brook University (US)
- Howard Hughes Medical Institute (US)
- Imperial College London (GB)
- Heidelberg University (DE)
- Icahn School of Medicine at Mount Sinai (US)
- NewYork–Presbyterian Hospital (US)
- Charité – Universitätsmedizin Berlin (DE)
- Yale University (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Modlin, Irvin
- Califano, Andrea
- ORCID
- Alvarez, Mariano J.
- Subramaniam, Prem S.
- Tang, Laura H.
- Grunn, Adina
- Aburi, Mahalaxmi
- Komissarova, Elena V.
- Hagan, Elizabeth A.
- Bodei, Lisa
- Clemons, Paul A.
- Diolaiti, Daniel
- Ghavami, Afshin
- Kaemmerer, Daniel
- Karan, Charles
- Kidd, Mark
- Kim, Hee C.
- Kunju, Lakshmi P.
- Langel, Ülo
- Li, Zhong
- Lee, Jeeyun
- Li, Hai
- LiVolsi, Virginia
- Rainey, Allison R.
- Realubit, Ronald B.
- Remotti, Helen
- Regberg, Jakob
- Roses, Robert
- Rustgi, Anil
- Sepulveda, Antonia R.
- Serra, Stefano
- Shi, Chanjuan
- Barberis, Massimo
- Bergamaschi, Roberto
- Chinnaiyan, Arul M.
- Ezzat, Shereen
- Frilling, Andrea
- Hommann, Merten
- Kim, Michelle K.
- Kung, Andrew L.
- Metz, David C.
- Milsom, Jeffrey W.
- Park, Young S.
- Schreiber, Stuart
- Wiedenmann, Bertram
- Califano, Andrea
- Venue
- Nature Genetics
- Published
- 2018-06-18
- Volume
- 50
- Issue
- 7
- Pages
- 979-989
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6421579
- OpenAlex
- W2808357284
- Cited by
- 210
- References
- 45
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 23 · 2023: 30 · 2022: 31 · 2021: 39 · 2020: 32 · 2019: 22 · 2018: 3
- FWCI
- 18.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Swedish Cancer Foundation
- National Institutes of Health (1s10od021764-01, 1s10od012351-01)
- Irving Medical Center, Columbia University
- National Cancer Institute (U54CA209997, P50CA095103, U01CA217858, P30CA008748, R35CA197745)
- National Center for Research Resources (G20RR030860)
- Topics
- Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- precision oncology, gastroenteropancreatic neuroendocrine tumors, drug prioritization, entinostat, immune evasion, gene expression profiling, metastatic neuroendocrine tumors
- MeSH terms
- Antineoplastic Agents, Benzamides, Histone Deacetylases, Humans, Intestinal Neoplasms, Pancreas, Pancreatic Neoplasms, Pyridines, Stomach Neoplasms, Cohort Studies, Neuroendocrine Tumors, Gastrointestinal Tract, Cell Line, Tumor, Histone Deacetylase Inhibitors, Precision Medicine
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