title: An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers.
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/LXRβ-full agonist selectively kills GBM cells in an LXRβ- 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.
authors.affiliation: 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, CA 92093, USA.
authors.forename: Genaro R
authors.initials: GR
authors.lastname: Villa
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hulce
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Ciro
authors.initials: C
authors.lastname: Zanca
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Bi
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegami
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Gabrielle L
authors.initials: GL
authors.lastname: Cahill
authors.affiliation: 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.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Lum
authors.affiliation: Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Masui
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Huijun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Rong
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Turner
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Hon
authors.affiliation: Small Molecule Discovery Program, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jenkins
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Martini
authors.affiliation: Department of Pharmacology, UCSD School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Armando
authors.affiliation: Department of Pharmacology, UCSD School of Medicine, La Jolla, CA 92093, USA; Department of Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Oswald
authors.initials: O
authors.lastname: Quehenberger
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: 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.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
authors.affiliation: 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.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.affiliation: Small Molecule Discovery Program, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Gahman
authors.affiliation: Small Molecule Discovery Program, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Shiau
authors.affiliation: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cravatt@scripps.edu.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: 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.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000494:pharmacology; D000071518:Liver X Receptors / Q000378:metabolism*; D051379:Mice; D016896:Treatment Outcome
chemical_list: C547927:2-(2-chloro-4-fluorobenzyl)-3-(4-fluorophenyl)-7-(trifluoromethyl)-2H-indazole; D007191:Indazoles; D000071518:Liver X Receptors; D002784:Cholesterol
keywords: brain cancer; cholesterol; glioblastoma; liver X receptor; metabolism; oxysterols