||5R01CA211939-04 Interpret this number
||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.
A conditional mouse expressing an activating mutation in NRF2 displays hyperplasia of the upper gastrointestinal tract and decreased white adipose tissue.
, Montgomery S.A.
, Schrank T.P.
, Simon J.M.
, Ptacek T.S.
, Tamir T.Y.
, Mulvaney K.M.
, Weir S.J.
, Nguyen T.T.
, Murphy R.M.
, et al.
The Journal of pathology, 2020 Oct; 252(2), p. 125-137.
Gene Expression Subtype Predicts Nodal Metastasis and Survival in Human Papillomavirus-Negative Head and Neck Cancer.
, Mazul A.L.
, Walter V.
, Hayes D.N.
The Laryngoscope, 2019 01; 129(1), p. 154-161.
RNA Oncoimmune Phenotyping of HPV-Positive p16-Positive Oropharyngeal Squamous Cell Carcinomas by Nodal Status.
, Farquhar D.
, Sheth S.
, Mazul A.
, Mamdani M.
, Hackman T.G.
, Hayes D.N.
, Zevallos J.P.
JAMA otolaryngology-- head & neck surgery, 2018-11-01; 144(11), p. 967-975.