Zevallos Lab

Principal Investigator:
Jose P. Zevallos, MD, Associate Professor, Otolaryngology-Head & Neck Surgery

Overview

The Zevallos lab is interested in identifying molecular drivers of carcinogenesis of HPV-positive oropharyngeal squamous cell carcinoma with poor oncologic outcomes, including patients with dual exposure to HPV and tobacco.  We seek a broad understanding of factors related to cancer susceptibility using knowledge derived from epidemiologic studies as well as fundamental cellular and molecular biology.

Research Projects

Development of a four-class, molecular subtyping diagnostic for HPV-negative head and neck cancer

Head and neck squamous cell carcinoma (HNSCC), including cancers of the oral cavity, pharynx, and larynx, is the sixth most common cancer worldwide worldwide. In the United States, approximately 60,000 new cases of HNSCC and 12,000 deaths are projected for 2015. A growing body of evidence demonstrates increasing incidence of oropharyngeal cancers, including a subset of human papillomavirus (HPV) associated tumors that demonstrate better prognosis. Despite the recent research interest in HPV-positive HNSCC, HPV-negative tobacco-associated cases continue to comprise the vast majority of HNSCC. Particularly in our state of North Carolina, where the population is more racially and socioeconomically diverse and where tobacco use remains high, HPV-negative HNSCC remains a significant public health problem. Oncologic outcomes for HPV-negative HNSCC remain poor and have not improved in the last 50 years, and there is a need to identify novel, personalized diagnostics and treatment strategies for patients with HPV-negative HNSCC. Four intrinsic HNSCC gene expression subtypes (basal (BA), classical (CL), mesenchymal (MS) and atypical (AT)) have been described, and provide an opportunity to inform patient management. These subtypes exhibit distinct differences in cell of origin, tumor drivers, proliferation, prognosis, and host immune response. In this application, we intend to develop and validate a clinic-ready diagnostic for HPV-negative HNSCC that includes both prognostic and predictive applications. While several therapeutic options exist for HNSCC including surgery, radiation therapy, and, chemotherapy, treatment selection remains empiric. With the exception of HPV status in oropharyngeal cancer, the molecular characteristics of individual tumors are generally not taken into account when deciding on treatment. This academic/industry collaboration will provide prognostic information based on biologic gene expression subtypes to guide decision-making for HPV-negative HNSCC, such as application of more aggressive surgery or radiation therapy based on tumor characteristics. We hypothesize that development efforts as described in this application will lead to a clinic-ready subtyping diagnostic, that combined with other mutation and clinical data, will provide both prognostic and predictive applications to guide the management of HNSCC.

Targeting the B7-H3 Immune Checkpoint Pathway in Head and Neck Squamous Cell Carcinoma

New immunotherapy treatment modalities have demonstrated dramatic results in a variety of malignancies, including head and neck squamous cell carcinoma (HNSCC). However, given the heterogeneity of treatment response, there is a need to understand mechanisms of immune escape and identify novel immune checkpoints for combination therapies. B7-H3 is a transmembrane protein expressed on many tissue and cell types that is upregulated in the tumor microenvironment on both antigen-presenting cells and tumor cells. Although not fully characterized, numerous studies support that B7-H3, like other members of the B7 family, inhibits CD4 and CD8 T cell activation, reduces proliferation of cytotoxic immune cells, and diminishes effector cytokine production. Based on these data a small number of early phase clinical trials with anti-B7-H3 monoclonal antibodies have been initiated. In this proposal, we seek to describe the mechanisms of B7-H3 induced immune evasion and treatment resistance in HPV (+) and (-) HNSCC. We have previously demonstrated differential B7-H3 expression by HPV status in HNSCC, with HPV (-) HNSCC associated with significantly elevated expression and worse oncologic outcomes. Furthermore, we have shown that B7-H3high expression in both HPV (+) and (-) HNSCC cell lines is associated with treatment resistance to cisplatin in vitro. We are currently evaluating the association between B7-H3 expression, immunosuppression, and poor survival using gene expression studies and immhistochemical analyses. We are also investigating the underlying mechanisms of B7-H3-induced treatment resistance in HPV (+) and HPV (-) HNSCC using B7-H3 activation and knockdown experiments on established HNSCC cell lines and PDX-derived cell lines.

Lab Team

  • Jose Zevallos, MD, MPH
  • Angela Mazul, PhD
  • Zixing Liu, PhD
  • Paul Zolkind, MD
  • Ricardo Ramirez, MD
  • Ben Wahle, MD
  • Jacob Clarke
  • Colleen M. Richmond

Current Funding

DEVELOPMENT OF A FOUR-CLASS, MOLECULAR SUBTYPING DIAGNOSTIC FOR HPV-NEGATIVE HEAD AND NECK CANCER
NCI: RO1CA211939 (Jose Zevallos, Principal Investigator)
Award Dates: 08/01/2017 – 07/31/2022

Description: Head and neck squamous cell carcinoma (HNSCC), including cancers of the oral cavity, pharynx, and larynx, is the sixth most common cancer worldwide worldwide. In the United States, approximately 60,000 new cases of HNSCC and 12,000 deaths are projected for 2015. A growing body of evidence demonstrates increasing incidence of oropharyngeal cancers, including a subset of human papillomavirus (HPV) associated tumors that demonstrate better prognosis. Despite the recent research interest in HPV-positive HNSCC, HPV-negative tobacco-associated cases continue to comprise the vast majority of HNSCC. Particularly in our state of North Carolina, where the population is more racially and socioeconomically diverse and where tobacco use remains high, HPV-negative HNSCC remains a significant public health problem. Oncologic outcomes for HPV-negative HNSCC remain poor and have not improved in the last 50 years, and there is a need to identify novel, personalized diagnostics and treatment strategies for patients with HPV-negative HNSCC. Four intrinsic HNSCC gene expression subtypes (basal (BA), classical (CL), mesenchymal (MS) and atypical (AT)) have been described, and provide an opportunity to inform patient management. These subtypes exhibit distinct differences in cell of origin, tumor drivers, proliferation, prognosis, and host immune response. In this application, we intend to develop and validate a clinic-ready diagnostic for HPV-negative HNSCC that includes both prognostic and predictive applications. While several therapeutic options exist for HNSCC including surgery, radiation therapy, and, chemotherapy, treatment selection remains empiric. With the exception of HPV status in oropharyngeal cancer, the molecular characteristics of individual tumors are generally not taken into account when deciding on treatment. This academic/industry collaboration will provide prognostic information based on biologic gene expression subtypes to guide decision-making for HPV-negative HNSCC, such as application of more aggressive surgery or radiation therapy based on tumor characteristics. We hypothesize that development efforts as described in this application will lead to a clinic-ready subtyping diagnostic, that combined with other mutation and clinical data, will provide both prognostic and predictive applications to guide the management of HNSCC.

THE EFFECT OF TOBACCO EXPOSURE ON GENETIC HETEROGENEITY IN HPV-POSITIVE OROPHARYNGEAL SQUAMOUS CELL CARCINOMA

McDonnell Genome Institute Pilot Grant (Zevallos, PI)
Award Dates:6/1/2018-5/31/2019

Description: The major goal of this study is to understand the mutational and gene expression characteristics of HPV-positive oropharyngeal squamous cell carcinoma in smokers and non-smokers.

Select Publications

  1. Han P, Gao F, Liu H, Liu Z, Shi Q, Troy JD, Owzar K, Lee W, Zevallos JP, Sturgis, EM, Wei Q. “Reduced mRNA expression of nucleotide excision repair genes in lymphocytes and risk of squamous cell carcinoma of the head and neck” Carcinogenesis 2017 Mar 31; epub ahead of print.
  2. Liu Z, Liu H, Han P, Gao F, Dahlstrom KR, Li G, Owzar K, Zevallos JP, Sturgis EM, Wei Q. “Apoptotic Capacity in Peripheral Blood Lymphocytes and Risk of Squamous Cell Carcinoma of the Head and Neck” Eur J Cancer. 2016; 72:166-176.
  3. Chera BS, Wang K, Monroe A, Galloway T, Amdur R, Hayes DN, Zevallos JP, Mendenhall WM. “Truth or Myth: Definitive Chemoradiotherapy doesn’t work for HPV/p16-negative Oropharyngeal Squamous Cell Carcinoma?” Oral Oncology Dec 2016 epub ahead of print.
  4. Zevallos JP, Yom SS. “Redefining the Role of Surgical Management in the Evolving Landscape of Oropharyngeal Cancer”, J Oncol Pract. 2016;12(11):1185-1187.
  5. D’Souza G, Anantharaman D, Beachler DC, Conway DI, Olshan AF, Wunsch-Filho V, Toporcov TN, Ahrens W, Wisniewski K, Merletti F, Tajara E, Zevallos JP, Levi JE, Weissler MC, Wright S, Carreira C, Brennan P. “Effect of HPV on Head and Neck Cancer Patient Survival, by Region and Tumor Site: A comparison of 1362 cases across three continents” Oral Oncol. 2016; 62:20-27.
  6. Wyss AB, Hashibe M, Lee YC, Chuang SC, Muscat J, Chen C, Schwartz SM, Smith E, Zhang ZF, Morgenstern H, Wei Q, Li G, Kelsey K, McClean M, Winn DM, Schantz S, Yu GP, Gillison M, Zevallos JP, Boffetta P, Olshan AF. “Smokeless Tobacco Use and the Risk of Head and Neck Cancer: Pooled Analysis of US Studies in the International Head and Neck Cancer Epidemiology Consortium”, Am J Epidemiology. 2016; epub ahead of print. PMID: 27744388
  7. Pena I, Chew EY, Landau BP, Breen JT, Zevallos JP, Vrabec JT. “Diagnostic Criteria for Detection of Vestibular Schwannomas in the VA Population”, Otol Neurotol. 2016;37(10):1510-1515.
  8. Mazul AL, Rodriguez N, Taylor JM, Desai D, Weissler MC, Brennan P, Anantharaman D, Abedi-Ardekani B, Olshan AF, Zevallos JP. “Prognostic Significance of HPV Genotype in Oropharyngeal Squamous Cell Carcinoma: Results from the Carolina Head and Neck Cancer Epidemiology Study”, Oral Oncol. 2016; 61:98-103.
  9. Mazul AL, Taylor JM, Divaris K, Weissler MC, Brennan P, Anantharaman D, Abedi-Ardekani B, Olshan AF, Zevallos JP. “Oral Health and HPV-Associated Head and Neck Cancer”, Cancer 2016; epub ahead of print.
  10. Wang K, Amdur RJ, Mendenhall WM, Green R, Aumer S, Hackman TG, Zanation AM, Zevallos JP, Patel SN, Weissler MC, Chera BS. “Impact of post-chemoradiotherapy superselective/selective neck dissection on patient reported quality of life”, Oral Oncol. 2016 Jul; 58:21-6.

Contact Us

Mailing address

660 S. Euclid Ave.
Campus Box 8115
St. Louis, MO 63110

Physical address

517 S. Euclid Ave.
Rm 904 (office), 1020 (lab)
St. Louis, MO 63110