Simultaneously inhibiting multiple nutrient acquisition pathways using synthetic sphingolipid compounds

Despite the advances in therapeutics targeting key players that drive cancer metabolism, clinical benefits of these therapies have been limited. As tumors consist of heterogeneous population of cells, targeting a specific oncoprotein may provide selective advantage to cancer cells that are not driven by that oncoprotein. Also, upregulation of anabolic pathways that are not being directly targeted may also contribute to development of resistance to the therapy. Instead of focusing on a specific metabolic protein, our lab is interested in striking cancer metabolism at its apex—cancer cells’ dependence on nutrients. To fuel constitutive anabolism and proliferation, cancer cells must have influx of nutrients. When nutrients become limiting, unlike non-transformed cell that can discontinue anabolic processes and become quiescent, cancer cells undergo metabolic chaos as oncogene-driven growth signals continue to force anabolism. Developing a therapy against this cancer-specific phenotype will have efficacy against broad classes of cancers as all cancers need nutrients to survive. In searching for a compound that can inhibit nutrient uptake, our lab has been focusing on sphingolipids, a class of bioactive lipid that plays important roles in cellular functions including membrane biology. In yeast, stress-induced nutrient transporter down-regulation is regulated by sphingolipid phytosphingosine. Sphingolipid ceramide down-regulates nutrient transporters in mammalian cells. A sphingolipid-derived compound FTY720 is also able to trigger surface amino acid and glucose transporter loss. FTY720, an FDA-approved drug for treatment of multiple sclerosis, has anti-cancer activities in a various cancer models. Unfortunately, FTY720 causes bradycardia at the doses needed for anti-neoplastic effects. However, mechanism by which FTY720 kills cancer cells is completely separate from its effect on heart rate. SH-BC-893 is a constrained analog of FTY720 that lacks its dose-limiting side effect but retains anti-neoplastic activities. SH-BC-893, like ceramide and FTY720, down-regulates surface nutrient transporters. In addition, SH-BC-893 induces cytoplasmic vacuolation secondary to mis-localization of lipid kinase PIKfyve. This blocks lysosomal degradation of autophagosomes and macropinosomes, alternate nutrient acquisition pathways cancer cells can use to adapt to nutrient stress triggered by loss of surface nutrient transporters. LDL receptors are also down-regulated and LDL degradation is blocked by SH-BC-893. Prostate cancers rely heavily on LDL uptake for growth and proliferation and are thereby very sensitive to SH-BC-893. Surprisingly, prostate cancer cells are resistant to amino acid and glucose withdrawal. Our ongoing works have uncovered that this is because PTEN loss in prostate cancers upregulates macropinocytosis. This previously-unappreciated macropinocytosis in prostate cancers requires AMPK activation. Our works demonstrate that prostate cancer cells can use macropinocytosis to consume necrotic debris to build protein biomass and lipid storage to survive and proliferate in low nutrient environment. These findings highlight cancer cells’ addiction to nutrients and offer insights into therapeutic opportunities for targeting this Achilles’ heels of cancer metabolism. SH-BC-893 prevents cancer cells from using nutrients taken up via macropinocytosis by inhibiting lysosomal degradation of macropinosomes. By simultaneously blocking import and lysosomal degradation of nutrients, this water soluble and orally bioavailable compound effectively starves cancer cells to death. Future investigations will help further fine-tune SH-BC-893 into a safe and effective anti-cancer agent that can overcome the problems of tumor heterogeneity and adaptive resistances seen with current metabolic therapies