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

Authors

Mariano J. Alvarez, Columbia University in the City of New York
Prem S. Subramaniam, Columbia University in the City of New York
Laura H. Tang, Memorial Sloan-Kettering Cancer Center
Adina Grunn, Columbia University in the City of New York
Mahalaxmi Aburi, Columbia University in the City of New York
Gabrielle Rieckhof, NYU Langone Health
Elena V. Komissarova, Columbia University in the City of New York
Elizabeth A. Hagan, Columbia University in the City of New York
Lisa Bodei, Memorial Sloan-Kettering Cancer Center
Paul A. Clemons, Broad Institute
Filemon S. Dela Cruz, Memorial Sloan-Kettering Cancer Center
Deepti Dhall, Cedars-Sinai Medical Center
Daniel Diolaiti, Memorial Sloan-Kettering Cancer Center
Douglas A. Fraker, University of Pennsylvania Perelman School of Medicine
Afshin Ghavami, PsychoGenics Inc.
Daniel Kaemmerer
Charles Karan, Columbia University in the City of New York
Mark Kidd, Wren Laboratories
Kyoung M. Kim, Samsung Medical Center, Sungkyunkwan University
Hee C. Kim, Samsung Medical Center, Sungkyunkwan University
Lakshmi P. Kunju, University of Michigan Medical School
Ülo Langel, Stockholms universitet
Zhong Li, Falconwood Foundation
Jeeyun Lee, Samsung Medical Center, Sungkyunkwan University
Hai Li, Columbia University in the City of New York
Virginia Livolsi, University of Pennsylvania Perelman School of Medicine
Roswitha Pfragner, Medizinische Universität Graz
Allison R. Rainey, Memorial Sloan-Kettering Cancer Center
Ronald B. Realubit, Columbia University in the City of New York
Helen Remotti, Columbia University in the City of New York
Jakob Regberg, Stockholms universitet
Robert Roses, University of Pennsylvania Perelman School of Medicine
Anil Rustgi, University of Pennsylvania Perelman School of Medicine

Document Type

Journal Article

Publication Date

7-1-2018

Journal

Nature Genetics

Volume

50

Issue

7

DOI

10.1038/s41588-018-0138-4

Abstract

© 2018 The Author(s). 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.

This document is currently not available here.

Share

COinS