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An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers.
Villa, Genaro R; Hulce, Jonathan J; Zanca, Ciro; Bi, Junfeng; Ikegami, Shiro; Cahill, Gabrielle L; Gu, Yuchao; Lum, Kenneth M; Masui, Kenta; Yang, Huijun; Rong, Xin; Hong, Cynthia; Turner, Kristen M; Liu, Feng; Hon, Gary C; Jenkins, David; Martini, Michael; Armando, Aaron M; Quehenberger, Oswald; Cloughesy, Timothy F; Furnari, Frank B; Cavenee, Webster K; Tontonoz, Peter; Gahman, Timothy C; Shiau, Andrew K; Cravatt, Benjamin F; Mischel, Paul S.
Affiliation
  • Villa GR; Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA; Medical Scientist Training Program, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla
  • Hulce JJ; Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Zanca C; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Bi J; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Ikegami S; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Cahill GL; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Gu Y; Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Lum KM; Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Masui K; Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
  • Yang H; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Rong X; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Hong C; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Turner KM; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Liu F; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Hon GC; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Jenkins D; Small Molecule Discovery Program, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Martini M; Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Armando AM; Department of Pharmacology, UCSD School of Medicine, La Jolla, CA 92093, USA.
  • Quehenberger O; Department of Pharmacology, UCSD School of Medicine, La Jolla, CA 92093, USA; Department of Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA.
  • Cloughesy TF; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Furnari FB; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA; Department of Pathology, UCSD School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093, USA.
  • Cavenee WK; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA; Department of Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093, USA.
  • Tontonoz P; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Gahman TC; Small Molecule Discovery Program, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Shiau AK; Small Molecule Discovery Program, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
  • Cravatt BF; Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cravatt@scripps.edu.
  • Mischel PS; Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA; Department of Pathology, UCSD School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093, USA. Electronic address: pmischel@ucsd.edu.
Cancer Cell ; 30(5): 683-693, 2016 Nov 14.
Article in En | MEDLINE | ID: mdl-27746144
ABSTRACT
Small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to their inability to achieve sufficient drug levels in the CNS. Targeting non-oncogene tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified. Here we demonstrate that the highly lethal brain cancer glioblastoma (GBM) is remarkably dependent on cholesterol for survival, rendering these tumors sensitive to Liver X receptor (LXR) agonist-dependent cell death. We show that LXR-623, a clinically viable, highly brain-penetrant LXRα-partial/LXRß-full agonist selectively kills GBM cells in an LXRß- and cholesterol-dependent fashion, causing tumor regression and prolonged survival in mouse models. Thus, a metabolic co-dependency provides a pharmacological means to kill growth factor-activated cancers in the CNS.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Neoplasms / Cholesterol / Glioblastoma / Liver X Receptors / Indazoles Type of study: Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2016 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Neoplasms / Cholesterol / Glioblastoma / Liver X Receptors / Indazoles Type of study: Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2016 Document type: Article