Glioblastoma multiforme (GBM) is characterized by major alterations in cellular metabolism, increasing their uptake and utilization of glucose coupled to enhanced lipogenesis and cholesterol uptake to meet the coordinately elevated anabolic and energetic demands imposed by rapid tumor growth. These metabolic alterations and the signaling pathways that control them, appear to be direct consequences of the genetic alterations that drive tumor growth and progression, thus providing a new array of potentially more specific and efficacious drug targets. We have recently demonstrated that amplification of the epidermal growth factor and its mutant form, EGFRvIII, up-regulate the expression of the low-density lipoprotein receptor (LDLR) to promote uptake of massive amounts of cholesterol into the cell;a process which is required for tumor growth and survival in vivo. We also showed that the Liver X Receptor (LXR), a critical determinant of LDLR levels, is a compelling novel therapeutic target in GBM. This proposal is designed to test a new, brain-penetrant LXR agonist, LXR-623 as a potentially potent, highly-specific anti-GBM therapy. We present exciting preliminary showing that LXR-623, potently kills every GBM cell line we have tested, while having no effect on normal human astrocytes, and we have demonstrated that this anti-tumor activity is mediated, at least in part, by up- regulation of the ATP-Binding Cassette Transporter 1 (ABCA1) to efflux cholesterol from the cell, and by up- regulation of the Inducible Degrader Of the LDLR (IDOL), which promotes ubiquitin-mediated degradation of LDLR and inhibition of cholesterol uptake. The overall goal of this project is to test the hypothesis that a recently identified agonist of the nuclear Liver X Receptor, LXR-623, which has been shown to cross the blood brain barrier in humans, will be a highly effective anti-GBM therapy, and to identify the underlying mechanisms by which it works. Specifically, Aim 1 will determine the efficacy of LXR-623 in inhibiting proliferation and inducing cell death in a panel of patient derived GBM neurospheres and secondary metastatic brain cancer cell lines.
Aim 2 will determine the mechanism and molecular determinants of LXR-623 antitumor efficacy through both a genetic and a novel sterol probe based unbiased approach, the latter with the Cravatt Laboratory at the Scripps Research Institute who is performing the proteome-wide mapping and activity-based profiling assays to assess the effect of the relevant signaling pathways and the impact of LXR-623 on cholesterol metabolism.
Aim 3, in collaboration with the Small Molecule Discovery (SMD) Group at the Ludwig Institute, which has the capability to develop clinical grade compounds and to perform all of the pharmacokinetic studies, will determine if LXR-623 inhibits tumor growth and induces tumor cell death in a patient derived GBM orthotopic xenograft mouse model. Taken together, this study will provide the pre-clinical basis for a phase I clinical trial of LXR-623 patients with GBM and will identify key molecular determinants underlying the effectiveness of LXR-623, providing a new landscape of drug targets in GBM.
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and is among the most lethal of all cancers. Patients have a median survival of 12-15 months despite surgery, radiation and chemotherapy, thus new treatments are needed. This project focuses on testing the efficacy of a brain penetrant Liver X Receptor agonist, LXR-623, which simultaneously inhibits cholesterol uptake and induces cholesterol efflux, and possesses highly potent and specific anti-tumor cell across all GBM cells we have tested. This project is designed to test the efficacy of LXR-623 in patient-derived GBM orthotopic models and to identify the mechanisms of its activity and determinants of its response. It is anticipated that successful completion of this project could lead towards development of LXR-623 as a novel agent for the treatment of GBM patients.
|Gu, Yuchao; Albuquerque, Claudio P; Braas, Daniel et al. (2017) mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT. Mol Cell 67:128-138.e7|
|Villa, Genaro R; Hulce, Jonathan J; Zanca, Ciro et al. (2016) An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers. Cancer Cell 30:683-693|
|Liu, Feng; Hon, Gary C; Villa, Genaro R et al. (2015) EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling. Mol Cell 60:307-18|
|Masui, Kenta; Tanaka, Kazuhiro; Ikegami, Shiro et al. (2015) Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance. Proc Natl Acad Sci U S A 112:9406-11|