New Drug Potentially Blocks HPV from Causing Head and Neck Cancer

Quintin Pan, PhD

A novel small molecule inhibitor called CH1iB may be able to block a mechanism that enables human papilloma virus (HPV) to cause head and neck cancer, according to new research published by the journal Oncogene.

According to the U.S. Centers for Disease Control, approximately 26,000 cases of cancer that can be attributed to HPV are diagnosed each year. Since the 1970s, the number of cases of head and neck cancer caused by HPV has tripled, suggesting that an epidemic might soon occur. Researchers have been trying to determine how the cancer is able to develop and ways in which to treat it.

Previous research had shown that the HPV E6 oncoprotein is able to inactivate p53, a key tumor suppressor protein via two mechanisms: E6 associates with E6AP, degrading p53 via the proteasome pathway. E6 also blocks the production of p300, a protein that allows for p53 acetylation, which enhances the stability and transcriptional activity of p53. Inactivating p53 is crucial for the formation of the tumor.

In this study, researchers targeted the interaction between HPV E6 and p300 to determine whether blocking this interaction might restore the function of p53. Research had shown that HPV E6 binds to p300 at three different domains: CH1, CH3, and C-terminal. The researchers found that if the expression of CH1 is abnormal, the interaction between HPV and p300 was blocked, which increased total and acetylated p53 levels and enhanced p53 transcriptional activity. Functional reactivation of p53 also occurs because of increased expression of p21, miR-34a, and miR200c, three well-recognized p53 targets.

The researchers determined that the overexpression of CH1 in HPV-positive head and neck squamous cell carcinoma has an anticancer effect that results in a decrease in cell proliferation and an increase in apoptosis.

“Our study revealed a new mechanism for p53 inactivation in HPV-positive head and neck cancer, and this allowed us to develop an agent that disrupts that interaction and reactivates p53 in HPV-positive head and neck cancer,” said Quintin Pan, PhD, associate professor and research director of the Head and Neck Oncology Program at The Ohio State University, Department of Otolaryngology-Head and Neck Surgery, in a statement.

The agent, CH1iB, targets binding site B in CH1 in HPV-negative head and neck cancer. In HPV-positive head and neck cancer cells, CH1iB enhanced p53 activity by 71% (P < .01) as well as p53 accumulation and acetylation. Modest but significant increases in levels of p21, miR-34a, and miR200c were also observed in cells lines treated with CH1iB. The association between HPV E6 and p300 was also reduced. Additionally, the potency of cis-platinum was increased in its effects on cell proliferation, survival, and apoptosis when CH1 was introduced, and CH1iB enhanced the anti-proliferative action of the agent.

“Our pre-clinical studies show CH1iB can reactivate p53 and eliminate HPV-positive head and neck cancer cells,” Pan said. “Taken together, our data suggest that we’ve discovered a novel approach for reactivating the p53 gene in HPV-positive head and neck cancer that may translate to other HPV-positive carcinomas.”

Xie X, Piao L, Bullock BN, et al. Targeting HPV16 E6-p300 interaction reactivates p53 and inhibits the tumorigenicity of HPV-positive head and neck squamous cell carcinoma [published online ahead of print March 11, 2013]. Oncogene. DOI:10.1038/onc.2013.25.