Researchers at MUSC Hollings Cancer Center have discovered a potentially powerful weapon in the fight against head and neck cancers. The new drug, still in preclinical studies, attacks cancer cells from within by damaging their mitochondria, the cells' energy factories.
The study, published in Cancer Research, was led by Besim Ogretmen, Ph.D., associate director of Basic Science at Hollings and director of Hollings' Lipidomics Shared Resource.
The multidisciplinary research team aimed to suppress tumor growth in head and neck squamous cell carcinoma, a cancer that develops in the cells lining the head and neck, such as the nose, mouth and throat. This highly aggressive form of cancer is treatment resistant, and a significant number of patients who receive standard care see their cancer return. Even when effective, these standard treatments can have broad impacts, killing noncancerous as well as cancerous cells and triggering debilitating side effects.
To overcome these issues, the researchers developed and tested a new compound called LCL768. LCL768 is a synthetic form of ceramide, a fat molecule naturally found in cells.
Ceramides are important for healthy cell function and have been shown to induce cell death under stress. Many head and neck cancers are low in this helpful fat, which relates to poorer outcomes in patients and contributes to the tumors' aggressive growth.
The drug's actions hinged on its ability to increase levels of a specific ceramide called C18-ceramide inside the mitochondria of cancer cells. When C18 levels increased, it set off a process called mitophagy, by which cells remove damaged or unnecessary mitochondria. Cancer cells' growth relies heavily on mitochondria, and when they are destroyed, the cancer cells run out of energy and die.
"LCL768 essentially cuts off the power supply to cancer cells," Ogretmen said. "Once their mitochondria are gone, the cells can no longer grow or survive."
In addition to breaking down mitochondria, LCL768 disrupted a key metabolic pathway. It did so by blocking fumarate, an important molecule in the cell's energy cycle. Without fumarate, cancer cells were further impaired in their energy production. Together, the combination of C18-ceramide buildup and fumarate depletion created a dual attack that induced cancer cell death.
"Our results reveal a metabolic weakness in these cancer cells," Ogretmen explained. "By triggering mitophagy and depleting fumarate, LCL768 shut down cancer cell survival mechanisms on two fronts, targeting both their mitochondria and metabolism."
"These findings represent a new frontier in cancer therapy. We're not only targeting cancer cells, we're dismantling their internal infrastructure and exploiting a fundamental weakness in how those cells manage energy and stress. That could make this treatment useful for a range of tumors."Besim Ogretmen, Ph.D.
The team tested LCL768 in mouse models of head and neck cancer and lab-grown tumors made from actual patient tissue. In both cases, the drug led to a significant increase in mitochondrial C18-ceramide.
After treatment, cancer cells showed clear signs of mitophagy and metabolic collapse, which led to slowed tumor growth. In support of this finding, providing the cells with fumarate almost completely reversed the inhibitory effects of LCL768 and led the tumors to regrow rapidly.
The researchers highlight LCL768 as a potential new way of targeting a vulnerability in head and neck cancers. What makes this approach unique is its efficiency - LCL768 both builds up tumor-killing ceramide and disrupts a key part of cancer cell metabolism. Importantly, the drug had little effect on healthy tissues, suggesting it may offer a safer alternative to chemotherapy and radiation.
"This precise targeting could lead to fewer side effects than chemotherapy or radiation, which often damage healthy cells as well as cancer cells," Ogretmen said. "The new drug homes in on a process cancer cells use to avoid normal cell death. Because healthy cells do not rely as heavily on these pathways, they are left mostly untouched."
The researchers are optimistic that the results could open new doors in cancer therapy, especially for tumors resistant to standard treatments. Reduced ceramide is a hallmark of many cancers, and boosting its levels via compounds like LCL768 could be part of a new class of treatments designed to target the metabolism and stress system of tumor cells.
"These findings represent a new frontier in cancer therapy," Ogretmen said. "We're not only targeting cancer cells, we're dismantling their internal infrastructure and exploiting a fundamental weakness in how those cells manage energy and stress. That could make this treatment useful for a range of tumors."
Although LCL768 is still in preclinical testing, meaning it hasn't yet been used with patients, the early results are promising. The team is now working to advance LCL768 toward clinical trials, with the hope that the novel approach may one day offer a lifeline to patients with hard-to-treat cancers.
"This research lays the foundation for developing a new class of anti-cancer agents that exploit mitochondrial vulnerability," Ogretmen said. "We are exploring how to optimize this approach for clinical use so that LCL768 or drugs like it could one day offer a safe, effective option for cancer patients who currently have few available treatments."
Natalia V. Oleinik, Firdevs Cansu Atilgan, Mohamed Faisal Kassir, Han Gyul Lee, Alhaji H. Janneh, Wyatt Wofford, Chase Walton, Zdzislaw M. Szulc, Elizabeth G. Hill, Alexander V. Alekseyenko, Huseyin Cimen, Jessica H. Hartman, Christina Voelkel-Johnson, Michael B. Lilly, John J. Lemasters, Norma Frizzell, Xue-Zhong Yu, Shikhar Mehrotra and Besim Ogretmen. Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression. Cancer Research. [2 September 2025]. doi: 10.1158/0008-5472.CAN-24-4042.
Grants from the National Institutes of Health supported this research.
