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From bed to bench and back to bed

A synthetic peptide designed to treat HPV-negative cancer

by Matthew Greseth

Dr. Besim Ogretmen
Dr. Besim Ogretmen

Patients with head and neck cancer, specifically oropharyngeal cancer, who are also positive for human papilloma virus (HPV) have been observed to respond significantly better to chemo-radiotherapy than patients who are HPV-negative. This observation is surprising because HPV infection leads to an increased risk of developing oropharyngeal cancer. To date, the reason for this dichotomy has not been well understood.

In an article in the August 2017 issue of EMBO: Molecular Medicine, MUSC researchers and clinicians report having identified one of the underlying mechanisms — expression of a specific viral protein leads to cell death through ceramide-induced mitophagy, a process that destroys the mitochondria.

“This study looked at both the clinical aspects as well as the mechanistic and therapeutic aspects of oral cancer. We are very excited about these findings because they represent what is happening in the clinic,” says Besim Ogretmen, Ph.D., Endowed Chair in Lipidomics & Drug Discovery in the SmartState® Center for Lipidomics, Pathobiology and Therapy and senior author for this study.

Ogretmen’s laboratory, which studies mitochondria and the signaling lipid ceramide, built upon the clinical observation that patients with HPV-positive cancer respond significantly better to treatment with cisplatin, a chemotherapeutic agent that resembles ceramide. The findings described in their recent work detail the molecular signaling cascade that induces cell death through a process termed ceramide-induced mitophagy in HPV-positive cancers.

Having described the mechanism by which HPV-positive cancer cells succumb to chemotherapy, the Ogretmen laboratory next wanted to determine if they could apply these findings to HPV-negative cancers, since patients with these cancers are much more likely to succumb to their disease.

In order to accomplish this, they developed a peptide that turns on the molecular signaling cascade, even in the absence of HPV. Treatment of HPV-negative oral cancer cells with cisplatin and this novel peptide led to increased cell death in a manner that was similar to treatment of HPV-positive cancer cells with cisplatin. Further experiments showed that this peptide was effective at killing HPV-negative cancer cells in a mouse model.

Overall, these results define the mechanism that underlies the increased efficacy in treating HPV-positive cancer with cisplatin and show that this improved efficacy can be achieved in HPV-negative cancer cells through co-treatment with this novel peptide.

This work required the coordinated collaboration of clinicians and basic science researchers and exemplifies the “bed – to bench – to bed” ideal that scientific research strives to achieve. Patients who were seen in the clinic were asked to donate the leftover cancer tissue from their surgery. Then the tissues were tested in the laboratory and in animal models. The results of these tests are now being taken back into the clinic (bedside) in an attempt to treat patients with HPV-negative head and neck cancers.

Given the profound impact of HPV status on survival, it has become clear that understanding the mechanisms driving the sensitivity of HPV-positive disease to cytotoxic therapies could provide the foundation for novel therapies in HPV-negative head and neck cancer,” says David M. Neskey, M.D., a surgeon at MUSC Hollings Cancer Center specializing in treatment of head and neck cancers.