Cancers – As a group, these viruses are the most common sexually transmitted infection in the United States.
HPV+ cancers account for more than 5% of malignancies worldwide and have had an increasing incidence in oropharyngeal squamous cell cancer (OPSCC). These are usually sensitive to the combination of radiation and cisplatin, which is usually curative for this disease.
Altered DNA repair mechanisms contribute to making HPV+ OPSCCs a group sensitive to these therapies, which destroy tumors by increasing reactive oxygen species generation beyond cellular antioxidant capacity, leading to uncontrolled DNA damage, proteins, and lipids.
Attempts to substitute anti-EGFR therapy for cisplatin have been unsuccessful, and radiation de-escalation efforts remain a work in progress. The ability to personalize therapy based on more accurate predictive biomarkers would greatly enhance treatment de-escalation efforts for this disease.
However, this innovation continues to be hampered by a poor understanding of the mechanisms underlying the responses.
Although cervical cancer in women has historically been the most common form of HPV-related cancer, CDC data shows that about four out of 10 HPV-induced cancers now occur in men.
The reason for this change is the increasing number of HPV-related throat cancers. These cancers affect men more often and are increasing rapidly in the developed world, where they are becoming more common than cervical cancer and are projected to continue to increase until the year 2060.
Penn Medicine scientists are working to change this with basic, translational, and clinical research projects that are establishing the healthcare system as an authority on HPV-related throat cancers. They found that levels of a certain HPV protein, E6, affect the number of mitochondria in both normal and cancer cells. Since mitochondria help cells withstand environmental stress such as radiation and chemotherapy, the results could have broad clinical implications.
E6-mediated downregulation of p53 reduces mitochondrial antioxidant capacity and thus sensitizes HPV+ OPSCCs to standard treatment, which is based on the induction of oxidative stress. The study provides evidence that different levels of fl-E6 in HPV+ cancers variably repress the PGC-1α/ERRα pathway, leading to diversity in mitochondrial mass that is likely to affect treatment response.
This finding provides a potentially novel mechanism by which levels of a viral oncoprotein may govern treatment outcomes in HPV+ OPSCC.
Treatment resistance can be prospectively identified by measuring fl-E6 levels and downstream components of the PGC-1α/ERRα mechanisms and mitigated through therapeutically targeted nodes in that pathway.
