@article{020de5053c7940b98b84684ad77aec10,
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.",
keywords = "brain cancer, cholesterol, glioblastoma, liver X receptor, metabolism, oxysterols",
author = "Villa, {Genaro R.} and Hulce, {Jonathan J.} and Ciro Zanca and Junfeng Bi and Shiro Ikegami and Cahill, {Gabrielle L.} and Yuchao Gu and Lum, {Kenneth M.} and Kenta Masui and Huijun Yang and Xin Rong and Cynthia Hong and Turner, {Kristen M.} and Feng Liu and Hon, {Gary C.} and David Jenkins and Michael Martini and Armando, {Aaron M.} and Oswald Quehenberger and Cloughesy, {Timothy F.} and Furnari, {Frank B.} and Cavenee, {Webster K.} and Peter Tontonoz and Gahman, {Timothy C.} and Shiau, {Andrew K.} and Cravatt, {Benjamin F.} and Mischel, {Paul S.}",
note = "Funding Information: G.R.V. would like to dedicate this manuscript to the loving memory of his father Genaro M. Villa. We thank Ms. Jennifer Tsoi for technical assistance with TCGA and microarray data. This work was supported by the National Cancer Institute F31CA186668 (G.R.V.) and by grants from the National Institute for Neurological Diseases and Stroke (NS73831 and NS080939), the Defeat GBM Program of the National Brain Tumor Society, the Ben and Catherine Ivy Foundation, and generous donations from the Ziering Family Foundation in memory of Sigi Ziering (P.S.M.). This work was also supported by the NIH CA132630 (B.F.C.). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = nov,
day = "14",
doi = "10.1016/j.ccell.2016.09.008",
language = "English (US)",
volume = "30",
pages = "683--693",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",
}