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

Al's Comment:

 This may be a new target for GBM treatment, which may use a few drugs already approved for other diseases. Should be quick and easy to prove... Might be a perfect project for our brain tumor virtual trial registry.


Posted on: 10/20/2016

. Cancer Cell. 2016 Oct 13. pii: S1535-6108(16)30443-3. doi: 10.1016/j.ccell.2016.09.008. [Epub ahead of print]
An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers.
Villa GR1, Hulce JJ2, Zanca C3, Bi J3, Ikegami S3, Cahill GL3, Gu Y4, Lum KM2, Masui K5, Yang H3, Rong X6, Hong C6, Turner KM3, Liu F3, Hon GC3, Jenkins D7, Martini M2, Armando AM8, Quehenberger O9, Cloughesy TF10, Furnari FB11, Cavenee WK12, Tontonoz P13, Gahman TC7, Shiau AK7, Cravatt BF14, Mischel PS15.
 
Author information:
1Department 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.
2Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
3Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
4Department 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.
5Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
6Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
7Small Molecule Discovery Program, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA.
8Department of Pharmacology, UCSD School of Medicine, La Jolla, CA 92093, USA.
9Department of Pharmacology, UCSD School of Medicine, La Jolla, CA 92093, USA; Department of Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA.
10Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
11Ludwig 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.
13Department 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.
14Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cravatt@scripps.edu.
15Ludwig 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.
 
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.
 
Copyright © 2016 Elsevier Inc. All rights reserved.
PMID: 27746144 [PubMed - as supplied by publisher]

 


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