Potentially novel options for treatment of HPV-attributable head and neck cancer

Squamous cell carcinomas of the head and neck originate in the mucosal linings of the oral cavity, the oropharynx, the larynx and hypopharynx. Most patients present with advanced stages of disease and are treated by surgery with postoperative (chemo) radiotherapy or chemoradiation, the combination of systemic cisplatin with concomitant locoregional radiotherapy, sometimes followed by salvage surgery. Patients who are unfit to receive chemoradiation are treated with a combination of cetuximab, an antibody inhibiting the EGF receptor, combined with locoregional radiotherapy, also called bioradiation.¹

Since last decades it has been shown that human papillomaviruses (HPV), known as the cause of cervical cancer, also cause a subgroup of head and neck cancers, most particularly those arising in the oropharynx. The proportion of HPV-attributable disease varies over the world, but appears to increase rapidly. In the USA and Canada the proportion of HPV+ve tumors is between 50 and 70%,^2,3 and in Europe usually somewhat less (30%). However, both the proportion and incidence rates of HPV+ve tumors are increasing.⁴ In the Netherlands the proportion increased from 5% in 1990 to 30% in 2010.⁵

Tumors caused by HPV infection form a different disease entity. They are different at the molecular and clinical level. HPV+ve tumors have a very favorable prognosis when compared with HPV−ve tumors. In fact the predominant factor that predicts prognosis of oropharyngeal cancer is the presence of HPV.^2,3 The prognosis is so favorable that two studies have been initiated to de-intensify therapy: the RTOG1016 trial in the USA and the De-ESCALaTE HPV study in Europe. In both studies patients with HPV+ve tumors are randomized between a chemoradiation arm and a bioradiation arm, with the aim to reduce toxicity in the bioradiation arm while maintaining favorable prognosis. However, it could be questioned whether cetuximab is the optimal substitute of cisplatin for HPV+ve tumors. In this issue Li and Johnson⁶ provide data that there might be other options at the horizon, also less toxic than cisplatin and more targeted to HPV.

The HPV genome encodes two viral oncoproteins named E6 and E7. The virus uses these proteins to create an S-phase environment in the host cell to allow viral replication using the host cell DNA replication machinery. The E6 protein binds and inactivates p53 and the E7 protein the pocket proteins pRb, p107 and p130, key proteins in the regulation of the G₁ and G₂ cell cycle checkpoints. These host proteins are subsequently ubiquinated and targeted for proteosomal degradation. Previously it has been shown that the knockdown of these E6/E7 genes inhibits proliferation of HPV-positive head and neck cancer cell lines.⁷ In this issue Li and Johnson,⁶ focusing on E6 and the p53 pathway, convincingly show that the cell cycle arrest and apoptosis caused by E6(/E7) knockdown is p53 and p21 mediated, as expected. Intriguingly, they also showed that bortezomib, a drug that inhibits proteosomal protein degradation and approved for treatment of multiple myeloma, was able to liberate and restore p53 and p21 expression specifically in HPV+ve cell lines, also causing cell death. This would suggest that bortezomib might be an interesting alternative for cisplatin in the combination with radiotherapy for HPV+ve tumors. Bortezomib is considerably less toxic than cisplatin.

Obviously a lot of additional work needs to be done before considering a clinical study. First, all data reported by Li and Johnson were collected by in vitro experiments. Therapy experiments in mouse models of xenografted cell lines or even better, human-in-mouse tumor models,⁸ are required. In addition, other questions remain. Although the authors convincingly showed that p53 and p21 are upregulated by bortezomib in HPV+ve cell lines and cause apoptosis, the HPV+ve cell lines are not more sensitive to bortezomib than the HPV-ve cell lines. That is somewhat unexpected. Moreover, one of the HPV+ve cell lines showed a G₁ arrest and the other two a G₂ arrest after bortezomib treatment. Although p53 and p21 play a role in both checkpoints, the nature of this difference should be solved, and also whether it is relevant in the context of irradiation. Bortezomib-based treatment protocols would include radiotherapy. Notwithstanding, irrespective of these considerations that clearly deserve attention, the observation is very interesting and should be further evaluated.

Li C, Johnson DE. Liberation of functional p53 by proteasome inhibition in human papilloma virus-positive head and neck squamous cell carcinoma cells promotes apoptosis and cell cycle arrest. Cell Cycle. 2013;12:923–34. doi: 10.4161/cc.23882.