Data-driven discovery of targets for bipotent anticancer drugs identifies Estrogen Related Receptor Alpha
Year: 2021
Type: preprint
Abstract: Drugs that kill tumors through multiple mechanisms have potential for broad clinical benefits, with a reduced propensity to resistance. We developed BipotentR, a computational approach to find cancer-cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway. Using tumor metabolism as proof-of-principle, BipotentR identified 38 candidate immune-metabolic regulators by combining epigenomes with bulk and single-cell tumor transcriptomes from patients. Inhibition of top candidate ESRRA (Estrogen Related Receptor Alpha) killed tumors by direct effects on energy metabolism and two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization (ii) antigen-presentation stimulation, recruiting CD8 + T cells into tumors. ESRRA is activated in immune-suppressive and immunotherapy-resistant tumors of many types, suggesting broad clinical relevance. We also applied BipotentR to angiogenesis and growth-suppressor pathways, demonstrating a widely applicable approach to identify drug targets that act simultaneously through multiple mechanisms. BipotentR is publicly available at http://bipotentr.dfci.harvard.edu/ . One-Sentence Summary BipotentR identifies targets for bipotent anticancer drugs, as shown by the energy and immune effects of ESRRA inhibition.
Authors: Avinash D. Sahu, Xiaoman Wang, Phillip Munson, Jan Klomp, Xiaoqing Wang, Shengqing Gu, Gege Qian, Phillip Nicol, Zexian Zeng, Chenfei Wang, Collin Tokheim, Wubing Zhang, Jingxin Fu, Jin Wang, Nishanth U. Nair, Joost Rens, Meriem Bourajjaj, Bas Jansen, Inge Leenders, Jaap Lemmers, Mark Musters, Sanne van Zanten, Laura van Zelst, Jenny Worthington, Myles Brown, Jun S. Liu, Dejan Juric, Cliff A. Meyer, Arthur Oubrie, X. Shirley Liu, David E. Fisher, Keith T. Flaherty
Institutions: Dana-Farber Cancer Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, State Key Laboratory of Medical Molecular Biology, Harvard University, Massachusetts General Hospital, National Cancer Institute
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3208636715