VCU Massey Comprehensive Cancer Center researchers showcase new mechanism to target glucosylceramide synthase in cancer therapy

RICHMOND, Va. — Nov. 9, 2026 — Researchers from VCU Massey Comprehensive Cancer Center recently exhibited that the inhibition of glucosylceramide synthase (GCS) can cause death in cancer cells that is independent of changes in pro-death ceramide levels. The findings, which were recently published in Cell Death Discovery, found that utilizing eliglustat, an FDA-approved drug, induced cell death in several cancer cell lines. Additionally, the findings demonstrated, for the first time, that GCS and its products had a pro-survival role in cancer cells.

“This is exciting, because it has clinical impact,” said Alexandra Straus, Ph.D., a post-doctoral fellow in the VCU Department of Cellular, Molecular and Genetic Medicine, who is also a collaborator on the paper. “As scientists that are at the bench, it’s important to think about how a clinical trial might be working, and these findings can help us identify potential biomarkers for understanding which patients might benefit most.”

What are the main findings of this research?

Researchers in the lab of Can Senkal, Ph.D., interim director of the Lipidomics and Metabolomics Shared Resource and member of the Cancer Biology research program at Massey, treated cancer cell lines that represent primary focuses in Massey’s catchment area - colon, ovarian and cervical cells - with eliglustat, a known inhibitor of GCS.

Eliglustat is typically used for the treatment of Gaucher disease type 1, a disease that occurs when a person has too little of the enzyme that breaks down glucosylceramide.

They found that eliglustat caused the cancer cells to die, not through ceramide accumulation as previously thought, but rather decreasing glucosylceramide in the cells. Further study by the Massey team showed that the cancer cells initially treated with eliglustat caused lysosomes to appear as enlarged vesicles because they could not degrade any cellular materials.

Because cancer cells rely on lysosomes to recycle cellular components, researchers showed that by inhibiting GCS via eliglustat, lysosomes cannot function properly, thereby inducing cancer cell death.

“Healthy cells need to have proper lysosomal function,” Senkal explained. “And cancer cells, since they grow so fast, they depend on this degradation process, so they need a healthy lysosome to keep up with their growth needs. And we think GCS or the complex glycosphingolipids have a role in maintaining the proper function of the lysosomes.

“And so, when the cancer cells do not have the GCS, they do not have the properly functioning lysosomes, and therefore, they die.”

Potential Impact

These findings could have clinical impact in several ongoing clinical trials that feature eliglustat in combination with immunotherapy. Additionally, this research could be used to develop biomarkers for patients and in determining cancer cell signatures in which these findings can best be applied.

What’s Next?

Researchers from Massey’s Cancer Biology and Development Therapeutics research programs are working to identify opportunities to further this research, likely by collaborating with outside companies or partners for clinical-grade compounding before further study could offer the opportunities for clinical trials.

Additionally, analysis of patient metabolites could provide a mechanism through which biomarker developments could be made in order to determine which patients have the lipid profile that might benefit from eliglustat.

Key terms:

• Ceramide
  • A fat molecule, ceramide has a large signaling function in cells
  • Ceramide causes cells to undergo death, which is positive for targeting cancer cells
  • It can exist as a regular molecule or have additions (like glucose)
• Glucosylceramide synthase
  • GCS is glucose combined with ceramide
  • Glucosylceramide does not cause cellular death as ceramide, but instead becomes a growth agent
  • Cancer cells that had more GCS are known to be more resistant to cancer therapy
• Lysosomes
  • Within the cell, lysosomes are organelles that help break down components within the cell, such as lipids or sugars
  • Different enzymes within the lysosomes can break down glucosylceramide and convert it back to ceramide

Collaborators

• Other VCU collaborators on the study included:
  • Sachin K. Kempelingaiah, M.S.
  • Stacey Nguyen
  • Sherina Premanandh

This research was funded by:

• NIH/NCI research grant R37 CA239532
• Harrison Scholar funds from Massey Comprehensive Cancer Center to C.E.S. NIH/NCI research fellowship T32 CA272382
• Lipidomics and Metabolomics, Flow Cytometry, and Microscopy Shared Resource Cores at the Massey Comprehensive Cancer Center are funded by NIH/NCI Cancer Center Support grant P30 CA016059