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Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways
Abstract:
Oncogenic mutations drive anabolic metabolism, creating a dependency on nutrient influx through transporters, receptors, and macropinocytosis. While sphingolipids suppress tumor growth by downregulating nutrient transporters, macropinocytosis and autophagy still provide cancer cells with fuel. Therapeutics that simultaneously disrupt these parallel nutrient access pathways have potential as powerful starvation agents. Here, we describe a water-soluble, orally bioavailable synthetic sphingolipid, SH-BC-893, that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways. SH-BC-893 activated protein phosphatase 2A (PP2A), leading to mislocalization of the lipid kinase PIKfyve. The concomitant mislocalization of the PIKfyve product PI(3,5)P2 triggered cytosolic vacuolation and blocked lysosomal fusion reactions essential for LDL, autophagosome, and macropinosome degradation. By simultaneously limiting access to both extracellular and intracellular nutrients, SH-BC-893 selectively killed cells expressing an activated form of the anabolic oncogene Ras in vitro and in vivo. However, slower-growing, autochthonous PTEN-deficient prostate tumors that did not exhibit a classic Warburg phenotype were equally sensitive. Remarkably, normal proliferative tissues were unaffected by doses of SH-BC-893 that profoundly inhibited tumor growth. These studies demonstrate that simultaneously blocking parallel nutrient access pathways with sphingolipid-based drugs is broadly effective and cancer selective, suggesting a potential strategy for overcoming the resistance conferred by tumor heterogeneity.
Insights
A novel synthetic sphingolipid, SH-BC-893, effectively targets cancer by blocking nutrient uptake and internal recycling. This dual action starves cancer cells, offering a promising, selective therapeutic strategy against diverse tumor types.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cancer cells rely on anabolic metabolism and nutrient influx via transporters, macropinocytosis, and autophagy.
- Sphingolipids can suppress tumor growth, but cancer cells utilize parallel nutrient pathways for survival.
- Targeting these parallel nutrient pathways offers a potential therapeutic strategy for cancer starvation.
Purpose of the Study:
- To investigate the efficacy of a synthetic sphingolipid, SH-BC-893, as a dual-action agent against cancer.
- To elucidate the molecular mechanisms by which SH-BC-893 inhibits nutrient access in cancer cells.
- To evaluate the selective toxicity of SH-BC-893 against various cancer models and normal tissues.
Main Methods:
- Administration of water-soluble, orally bioavailable synthetic sphingolipid SH-BC-893.
- Assessing nutrient transporter internalization and lysosome-dependent nutrient generation.
- Investigating the activation of protein phosphatase 2A (PP2A) and mislocalization of PIKfyve and PI(3,5)P2.
- Evaluating cancer cell killing in vitro and in vivo, including Ras-driven and PTEN-deficient tumors.
- Assessing the impact on normal proliferative tissues.
Main Results:
- SH-BC-893 induced nutrient transporter internalization and blocked lysosomal degradation pathways.
- The drug activated PP2A, leading to PIKfyve mislocalization and PI(3,5)P2 reduction, causing cytosolic vacuolation and blocking lysosomal fusion.
- SH-BC-893 selectively killed Ras-driven cancer cells and PTEN-deficient prostate tumors.
- Normal tissues were unaffected at doses that inhibited tumor growth.
Conclusions:
- Simultaneous blockade of parallel nutrient access pathways with SH-BC-893 is a broadly effective and cancer-selective strategy.
- Sphingolipid-based drugs offer a potential approach to overcome therapeutic resistance driven by tumor heterogeneity.
- SH-BC-893 demonstrates significant anti-tumor activity with minimal toxicity to normal tissues.
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