Studies on human papillomavirus-positive head and neck cancer – Tina Dalianis' team

Human papillomavirus positive oropharyngeal cancer is increasing in incidence and despite its good prognosis not all patients are cured. Likewise, for high risk neuroblastoma and medulloblastoma not all cancers are cured. We focus on finding biomarkers that are prognostic and predictive for treatment responses e.g. to immune check inhibitors and that are also useful for targeted therapy. We have promising data on synergistic effects with targeted therapies against the above cancers.

Part of the:

Our research

We focus on human papillomavirus (HPV)-positive head and neck cancer, particularly tonsillar and base of tongue squamous cell carcinoma (TSCC and BOTSCC). While more than 200 HPV types exist, only a subset are oncogenic, with HPV16 and HPV18 being the most well-known for causing cervical cancer, and included in today’s HPV vaccines. However, in addition to established risk factors such as smoking and alcohol, HPV has a causal link to oropharyngeal cancer, where TSCC and BOTSCC dominate. We and others have demonstrated that HPV-positive tumors have significantly better survival outcomes compared to HPV-negative cancers, with approximately 80% versus 40% five-year disease-specific survival. At the same time, the incidence of HPV-positive TSCC and BOTSCC has increased epidemically over the recent decades.

Despite improved outcomes in HPV-positive disease, treatment of head and neck squamous cell carcinoma (HNSCC) often involves intensified radiotherapy combined with chemotherapy, with many severe side effects. This approach has not improved outcomes for patients with poor prognosis, and some patients are likely overtreated. A key aim of our research is therefore to improve patient stratification by identifying biomarkers that, together with HPV status, can better predict treatment response or that can be useful for targeted therapy.

Ongoing projects

We have previously conducted biomarker studies in TSCC and BOTSCC patient cohorts, where we identified several prognostic markers, including HLA class I, CD44, LRIG, CD8 tumor-infiltrating lymphocytes, and HPV16 E2 mRNA expression. Individually or in combination, these markers can identify a subset of 20–30% of patients with a very high likelihood of complete response. By integrating multiple biomarkers with HPV status through mathematical modeling, 40–56% of patients who respond to therapy can be identified. Using DNA and RNA sequencing, we identified additional markers, including frequent mutations in PIK3CA and FGFR3, both of which are targetable proteins, and a CDC27 deletion variant associated with relapse. 

To explore therapeutic opportunities, we use in vitro models of HPV-positive and HPV-negative TSCC and BOTSCC. Tumor cell lines grown as monolayers and spheroids are tested for sensitivity to a range of targeted agents, including inhibitors of PI3K, FGFR, CDK4/6, PARP, WEE1, and CDC27-related pathways. These studies have demonstrated dose-dependent responses and, in several cases, additive or synergistic effects when therapies are combined or used together with chemotherapy. With this approach, we hope to identify whether drugs used today in other types of tumors, or against newly disclosed mutated genes, can be used for TSCC and BOTSCC. 

A current main focus of our research is the use of circulating cell-free HPV DNA (cfHPV-DNA) as a biomarker for monitoring disease. Using droplet digital PCR, we have shown that cfHPV-DNA can be detected in the plasma of nearly all patients with HPV-positive TSCC/BOTSCC as well as other HPV-positive head and neck cancers. Moreover, upon treatment, cfHPV-DNA decreased and disappeared. From this, we were able to identify a group of patients with a fast treatment response and patients with residual disease, and we could also detect relapses earlier than with the present clinical routine. We are currently exploring the clinical implementation of cfHPV-DNA monitoring, which in the future may complement or replace the current follow-up methods, as well as reduce the need for frequent follow-up visits.

By combining the cfHPV-DNA data with our previously identified prognostic markers, we further aim to improve individualized therapy. For example, patients with rapid cfHPV-DNA clearance and favorable biomarkers may be candidates for treatment de-escalation to reduce toxicity. Conversely, patients with residual disease or relapse may lack favorable markers or harbor high-risk alterations such as the deletion variant of CDC27, and could benefit from targeted therapies.

Overall, our goal is to improve prognostication and tailor therapy for the growing population of patients with HPV-related TSCC and BOTSCC. By combining molecular biomarkers, genomic profiling, and liquid biopsy approaches, we aim to increase survival while minimizing treatment-related side effects and improving quality of life.