An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers

Genaro R Villa; Jonathan J Hulce; Ciro Zanca; Junfeng Bi; Shiro Ikegami; Gabrielle L Cahill; Yuchao Gu; Kenneth M Lum; Kenta Masui; Huijun Yang; Xin Rong; Cynthia Hong; Kristen M Turner; Feng Liu; Gary C Hon; David Jenkins; Michael Martini; Aaron M Armando; Oswald Quehenberger; Timothy F Cloughesy; Frank B Furnari; Webster K Cavenee; Peter Tontonoz; Timothy C Gahman; Andrew K Shiau; Benjamin F Cravatt; Paul S Mischel

doi:10.1016/j.ccell.2016.09.008

An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers

Cancer Cell. 2016 Nov 14;30(5):683-693. doi: 10.1016/j.ccell.2016.09.008. Epub 2016 Oct 13.

Authors

Genaro R Villa¹, Jonathan J Hulce², Ciro Zanca³, Junfeng Bi³, Shiro Ikegami³, Gabrielle L Cahill³, Yuchao Gu⁴, Kenneth M Lum², Kenta Masui⁵, Huijun Yang³, Xin Rong⁶, Cynthia Hong⁶, Kristen M Turner³, Feng Liu³, Gary C Hon³, David Jenkins⁷, Michael Martini², Aaron M Armando⁸, Oswald Quehenberger⁹, Timothy F Cloughesy¹⁰, Frank B Furnari¹¹, Webster K Cavenee¹², Peter Tontonoz¹³, Timothy C Gahman⁷, Andrew K Shiau⁷, Benjamin F Cravatt¹⁴, Paul S Mischel¹⁵

Affiliations

¹ 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.
² Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
⁴ 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.
⁵ Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
⁶ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Small Molecule Discovery Program, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
⁸ Department of Pharmacology, UCSD School of Medicine, La Jolla, CA 92093, USA.
⁹ Department of Pharmacology, UCSD School of Medicine, La Jolla, CA 92093, USA; Department of Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA.
¹⁰ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
¹⁵ 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: [email protected].

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.

Keywords: brain cancer; cholesterol; glioblastoma; liver X receptor; metabolism; oxysterols.

Publication types

Comment

MeSH terms

Animals
Brain Neoplasms / drug therapy*
Brain Neoplasms / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cholesterol / metabolism*
Female
Glioblastoma / drug therapy*
Glioblastoma / metabolism
Humans
Indazoles / administration & dosage*
Indazoles / pharmacology
Liver X Receptors / metabolism*
Mice
Treatment Outcome

Substances

2-(2-chloro-4-fluorobenzyl)-3-(4-fluorophenyl)-7-(trifluoromethyl)-2H-indazole
Indazoles
Liver X Receptors
Cholesterol

Abstract

Publication types

MeSH terms

Substances

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