Fatty Acid Synthase and lipophagy as therapeutic targets of glioblastoma

• Applicants: Professor Dr. Donat Kögel; Professorin Dr. Irmgard Tegeder
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528480730

Blocking de novo fatty acid synthesis has been considered as an anti-cancer strategy since the discovery of orlistat-mediated effects. Recent work shows that brain tumours including GBM and brain metastases heavily rely on de novo fatty acid synthesis via fatty acid synthase (FASN). A novel FASN inhibitor, TVB-2640 (Denifanstat) has recently entered a phase-3 clinical trial for glioblastoma (GBM). It is now commercially available for preclinical research and has overcome previous pharmacokinetic and toxicity limitations. But tumour cells may escape from lipid shortage via reutilization from lipid droplets. Therefore, the present project shall investigate anti-GBM efficacy of TVB-2640 in vitro and in vivo alone and in combination with chloroquine and define the underlying molecular determinants of GBM susceptibilities. The molecular studies address lipidomic and metabolomic patterns, mitochondrial respiration, cell viability and autophagy pathways in high-to-low sensitive GBM cells. Our preliminary data have revealed strong synergistic effects of TVB-2640 and the autophagy inhibitor, cholorquine (CQ). Hence, the project shall specifically address the ability of the tumour cells to reutilize lipids from lipid droplets (LD) as putative escape mechanism. To address lipophagy, knockdown/knockout cell lines of candidate LD targeting proteins (e.g. spartin) and of autophagy proteins (ATG5/7), and co-therapy with TVB-2640 + CQ shall be tested in GBM cell lines and in organotypic brain slice cultures. Furthermore, we investigate the in vivo therapeutic efficacy of TVB-2640 monotherapy and TVB-2640+CQ co-therapy (versus CQ mono, versus placebo, 4 groups) in orthotopic GBM xenograft and syngeneic models in mice. Readouts shall be survival, tumour growth, histology, cognitive behaviour and final lipidomic and metabolomic patterns. FASN inhibition causes a state of tumour starvation. To reveal how lipid shortage affects clinical GBM, lipidomic and metabolomic data and histology of auto/lipophagy shall be obtained from syngeneic and xenotransplant mouse GBM and from clinical GBM samples of patients who participated in the ERGO3 trial (collaboration with Dept. of Neurooncology, FFM) that addresses the impact of fasting to enhance anti-GBM treatments. We plan to establish mass spectrometry imaging (MSI) for visualization of lipid gradients across GBM sections and surrounding brain tissue. Together, the studies shall unravel the putative usage of FASN inhibition for GBM treatment.

• DFG Programme: Research Grants