Novel lipid and glutamine metabolism-based combination therapies for glioblastoma

ABSTRACT Glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis, necessitating the urgent development of novel therapies. Recent studies indicate that GBM requires elevated lipid levels for rapid growth. Our research has revealed that GBM enhances the uptake of low-density lipoprotein (LDL) by upregulating the LDL receptor, utilizing lysosomal breakdown to access cholesterol and fatty acids (FAs) for growth. Additionally, GBM contains abundant lipid droplets (LDs), which are also hydrolyzed in lysosomes to release stored cholesterol and FAs, further promoting GBM growth. Given the reliance of GBM on lysosomal breakdown of LDL and LDs for essential lipid supply, inhibiting lysosome function to block cholesterol/FAs supply might be an effective approach to target GBM. Through drug screening, we identified pimozide, a brain- penetrant antipsychotic medication, as a potent agent that inhibits lysosomal function, effectively suppressing LDL and LD hydrolysis in GBM cells. Surprisingly, inhibition of lysosome function unexpectedly increased the expression of the glutamine transporter ASCT2, enhancing glutamine uptake/consumption. This was accompanied by upregulation of enzymes involved in cholesterol and FA synthesis. Promisingly, our initial in vivo tests showed that inhibiting glutamine uptake/consumption or lipogenesis, in combination with pimozide, effectively inhibited tumor growth in orthotopic GBM models without observed toxicities in mice. These findings support our hypothesis that, in response to reduced lipid supply from lysosomes, GBM enhances glutamine uptake and consumption to promote de novo lipid synthesis, ensuring survival. We further hypothesize that inhibition of the glutamine uptake/consumption-lipogenesis axis combined with lysosome inhibition is an effective approach to target GBM. Our proposed studies aim to elucidate the molecular mechanisms upregulating glutamine uptake/consumption and lipogenesis in GBM cells upon lysosome inhibition (Aim 1), and to validate the therapeutic efficacy of targeting these pathways in combination with lysosome suppression by pimozide in GBM in vitro and in vivo (Aim 2). Successful completion of this study will provide valuable insights into the intrinsic connection between lysosome function, glutamine metabolism, and lipid synthesis in GBM, potentially paving the way for new therapeutic approaches to target this deadly cancer.