Human papillomavirus is one of the most widespread viral infections in the world and a leading cause of cervical cancer, responsible for an estimated 266,000 cervical cancer deaths globally in 2012 alone. In the United States, approximately 12,200 women are diagnosed with cervical cancer each year despite the availability of routine screening through Pap smears and HPV DNA testing. While highly effective vaccines exist, including the nine valent Gardasil 9, these vaccines must be administered before a person becomes sexually active and offer no therapeutic benefit against existing human papillomavirus infections. New research from the University of Alabama at Birmingham now points to a cancer drug already approved for other conditions as a potential treatment for active HPV infections.
Why Treating Human Papillomavirus Has Been So Difficult
One of the fundamental obstacles in human papillomavirus research has been the inability to propagate the virus in conventional cell culture systems, which has severely limited the ability to study its pathogenic effects and test potential treatments. The laboratory of Louise Chow and Thomas Broker at UAB addressed this barrier by developing a raft culture system, in which primary human keratinocytes are grown at an air media interface over two to three weeks to produce a fully differentiated human squamous epithelium. In 2009, the lab achieved a breakthrough by successfully culturing HPV 18 infected keratinocytes in this system, enabling robust viral DNA amplification and the production of infective viral progeny. This model became the foundation for preclinical investigation of anti human papillomavirus agents.
How Vorinostat Targets Human Papillomavirus DNA Replication
The research team, led by N. Sanjib Banerjee, assistant professor of Biochemistry and Molecular Genetics at UAB, hypothesized that inhibitors of histone deacetylases, known as HDACs, could block human papillomavirus DNA amplification. The reasoning was grounded in the known mechanism by which HPV replicates: the virus reactivates host DNA replication machinery in differentiated epithelial cells, co opting the same proteins and substrates used for chromosomal replication to amplify its own viral genome. HDAC activity is required for chromosomal DNA replication, which means that HDAC inhibitors could disrupt both chromosomal and viral replication simultaneously.
Vorinostat, an HDAC inhibitor already approved for the treatment of certain lymphomas, was tested in the HPV 18 raft culture model. The results showed that vorinostat effectively inhibited HPV 18 DNA amplification and virus production. Importantly, the drug also induced apoptosis, the form of programmed cell death, in a portion of the differentiated infected cells. Uninfected cells in the raft culture, which do not replicate their DNA, were largely spared, suggesting a meaningful degree of selectivity. Similar results were obtained with two additional HDAC inhibitors, belinostat and panobinostat.
Human Papillomavirus High Risk Strains and Cancer Cell Lines
Beyond the HPV 18 findings, the UAB team also tested vorinostat in raft cultures derived from dysplastic and cancer cell lines carrying HPV 16, the other most prevalent high risk human papillomavirus strain. HPV 16 and HPV 18 together are responsible for the majority of anogenital and oropharyngeal cancers caused by human papillomavirus. Vorinostat caused extensive cell death in these HPV 16 cultures as well, though the researchers noted that further investigation would be required to confirm whether HDAC inhibitors could be therapeutically useful in treating HPV associated dysplasias and cancers, not just benign infections.
What This Means for Human Papillomavirus Treatment
The implications of this research extend in two directions. First, HDAC inhibitors like vorinostat may offer a viable pharmacological strategy for treating active human papillomavirus infections by blocking viral replication and reducing infectious transmission. Second, vorinostat’s established role as a drug delivery vehicle in cancer biology suggests a potential combination approach, where Nischarin expressing exosomes or similar targeted carriers could be used alongside HDAC inhibitors to enhance therapeutic precision.
According to Banerjee, safe, effective, and inexpensive therapeutic agents are urgently needed for human papillomavirus infections that existing vaccines cannot address. This research positions HDAC inhibitors as promising candidates for that role, pending further validation in additional preclinical and eventually clinical settings.
FOMAT conducts clinical research across multiple therapeutic areas including oncology and infectious disease. To learn more about active studies, visit FOMAT’s patient studies page.
For the full source, see the original article at R&D Magazine.