Jacob Miller, MD

Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic Lerner Research Institute

Head and Neck Cancer

Pilot Grant

Molecular and Serologic Biomarkers of Latent HPV Infection for Early Detection and Risk-Adapted Treatment of Oropharyngeal and Anal Carcinoma

Chronic viral infections cause approximately 20% of solid tumors worldwide. Lifelong human papillomavirus (HPV) infection is responsible for the vast majority of cervical, oropharyngeal (throat), and anal cancers. Although HPV vaccination exists, millions of unvaccinated adults older than 30 are chronically infected with HPV and will go on to develop these tumors decades later. No treatment exists for these chronic infections, but cervical cancer screening has successfully reduced deaths because of the ability to remove precancerous lesions. Unfortunately, no such screening methods exist for oropharyngeal/anal cancers. As a result, many individuals with chronic HPV infection will go on to develop these life-threatening tumors and suffer from the long-term side effects of surgery, radiation, and chemotherapy. It is highly desirable to develop better methods of detecting HPV in the blood, saliva, and excretions of individuals with precancerous lesions and early-stage tumors.

We propose three approaches to advance the treatment and screening for these cancers. First, we will develop a highly sensitive test that can detect HPV DNA in the blood of patients with oropharyngeal/anal cancer. Currently, all treatments for these tumors are based on pre-treatment imaging (stage) rather than blood or tissue biomarkers. In contrast, other tumors (prostate, thyroid) use highly sensitive biomarkers to estimate prognosis, guide treatment decisions, and follow response after treatment. Rather than developing an expensive and complex test that can only be used in a research laboratory, we will validate and implement our assay in a clinical laboratory with faster turnaround times and low costs.

Second, we will develop better methods to screen for oropharyngeal/anal cancers. Current testing and screening approaches for cervical cancer are not well-suited for oropharyngeal/anal cancers due to variety of factors. Our experimental approach will search for specific HPV antibodies and HPV genomic changes in the blood of patients with benign infection, precancerous infection, and invasive cancer. In contrast to PCR-based tests for cervical cancer which report only the presence or absence of HPV, our research will identify markers of precancerous change that warrant further evaluation. Thereafter, we will develop noninvasive tests that can be introduced in clinical laboratories to detect specific HPV antibodies and gene silencing which are suggestive of cancer. As part of this research, we will explore the feasibility of having patients self-collect samples at home rather than in the clinic.

Our third objective aims to help design the first oropharyngeal cancer screening trials. There is currently no framework to model the progression of benign oropharyngeal HPV infection to early-stage cancer. Such a model would be required to determine if, when, and how to screen the population to identify early-stage disease. In a similar virally-associated cancer, we previously created a flexible model using economic and public health data. The result of our prior study helped to design cost-effective screening programs in southern China.

Overall, the outcome of our proposed research would be to integrate HPV biomarkers into modern treatment regimens, and work to develop new screening strategies for the millions of adults who will eventually suffer from these diseases.

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