Abstract B097: Dysregulated mevalonate and cholesterol synthesis is a therapeutic vulnerability in glioblastoma

Abstract

Abstract A hallmark of cellular transformation is the evasion of contact-dependent inhibition of growth. To find new therapeutic targets for glioblastoma, we looked for pathways that are inhibited by high cell density in normal astrocytes but have lost this regulation in glioblastoma stem-like cells. Here we report that at high cell density, normal astrocytes turn off mevalonate and cholesterol synthesis but glioma cells keep these pathways active. Correspondingly, mevalonate and cholesterol pathway upregulation is associated with poor prognosis in glioblastoma patients. Densely plated glioma cells increase oxygen consumption to synthesize cholesterol, resulting in a decrease in reactive oxygen species, TCA cycle intermediates, and ATP, but without a compensating increase in aerobic glycolysis. This constitutive cholesterol synthesis is controlled by the cell cycle, as it can be turned off by cyclin-dependent kinase inhibitors and it correlates with disabled cell cycle control though loss of p53 and RB. Mevalonate and cholesterol pathway activation promoted aberrant growth through the LXR and Hippo pathways. Finally, glioma cells, but not astrocytes, are sensitive to cholesterol synthesis inhibition downstream of the mevalonate pathway, suggesting that specifically targeting cholesterol synthesis might be an effective treatment for glioblastoma. Citation Format: Diane M. Kambach, Alan S. Halim, A. Gesine Cauer, Qian Sun, Carlos A. Tristan, Aparna H. Kesarwala, Uma Shankavaram, Eric Batchelor, Jayne M. Stommel. Dysregulated mevalonate and cholesterol synthesis is a therapeutic vulnerability in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B097.