Oral and Salivary Cancer Biology Program
Integrative Biology and Infectious Disease Branch
Division of Extramural Research
The goal of this initiative is to accelerate translation of research to improve early detection of head and neck cancers (HNC). This initiative will encourage development, evaluation, and validation of biomarkers for risk assessment, detection, and molecular diagnosis and prognosis of early HNC.
Head and neck cancers (HNC), the sixth leading type of cancers by incidence worldwide, is a heterogeneous group of malignancies that arise in the oral and nasal cavities, paranasal sinuses, pharynx, larynx, and salivary glands. In the United States, more than 65,000 individuals are newly diagnosed with HNC every year. Head and neck squamous cell carcinoma (HNSCC) accounts for about 80% of all HNC; less common HNC types include adenocarcinomas (<15%), lymphomas (<5%), melanomas (<3%), and salivary gland carcinomas (<3%). The primary risk factors associated with HNC include tobacco use, alcohol consumption, and viral infections such as from Human Papilloma Virus (HPV), Epstein-Barr Virus (EBV), and Human Immunodeficiency Virus (HIV).
While cancer prevention programs such as tobacco control and smoking cessation have decreased the overall HNC incidence, a steady increase in HPV associated tongue and oropharyngeal cancers have been identified in recent years. Despite improved treatment, the overall five-year survival rate for HNC patients remains around 40- 50%. HPV(+) HNC responds better to treatment, and HPV(+) HNC patients demonstrate favorable prognosis, with a 28% reduced risk of death and almost 50% reduced risk of local recurrence when compared with HPV(-) HNC patients. Despite a favorable initial response to therapy, up to 30% of HPV(+) HNC patients experience recurrence. Treatment of late-stage HNC involves intense surgical intervention causing disfiguring, or chemo- and radiotherapies, causing severe morbidity, compromising the quality of life. The low survival rate and low quality of life for HNC patients are partly due to limited detection of early disease and limited interventional options for HNC premalignancy. HNC patients diagnosed at an early-stage experience significantly improved survival rates and quality of life. The conventional visual/tactile exam coupled with a tissue biopsy is the current gold standard for lesion assessment, but this method has significant limitations due to its inability to reliably discriminate between reactive or inflammatory lesions verses premalignant or early malignant lesions. Early detection and diagnosis of HNC remain a significant challenge because early development of cancer may not cause any symptoms, may appear as benign lesions or may reside in deep cavities. Therefore, improvement of early detection and biomarker research with definitive diagnostic value is much needed.
During the past two decades the advancements of high throughput technologies and large data computation accelerated the understanding of the most comprehensive genomic and molecular portraits of human cancers. The Cancer Genome Atlas (TCGA) program, together with other large collaborative functional genomic and proteomic projects, have generated over 2.5 petabytes of genomic, epigenomic, transcriptomic, and proteomic datasets of 33 major cancer types, including HNC. These large-scaled open-source datasets provide unique and complex information codes to specifically match the tumor genetic or expression defects with patient clinical outcomes, which could lead to tailored biomarker identification for early diagnosis and treatments.
Gaps and Opportunities
The predominant precursor for HNC is tissue dysplasia. Treatment approaches for dysplastic lesions include observation, excision, phototherapy, laser therapy, cryotherapy, or pharmacological therapy. Estimates of the propensity for lesions to progress to cancer vary considerably, and in most cases, there are limited biomarkers that can predict which lesions will progress to cancer and which will not. In addition, tumor recurrence and metastasis after treatment, and the development of secondary tumors are risk factors for poor prognosis of HNC patients. Better understanding of the molecular characteristics of dysplastic lesions and early recurrence are needed to provide biomarkers that improve lesion classification relevant to predicting cancer progression, which could have a significant impact on cancer prevention and treatment optimization.
Research topics that are relevant to this initiative, but are not limited to, include:
- Discover/develop molecular, genomic, immunological, cellular, and imaging signatures for early cancer lesion classification.
- Discover/evaluate biomarkers and technologies complementing currently clinical methods to increase sensitivity and specificity for assessing risk for early cancer development and progression, and early cancer recurrence and metastasis after treatments.
- Develop novel tools and methods for detecting molecular, immunological, and cellular hallmarks in bodily fluids obtained by non-invasive or minimally invasive methods.
- Integration of high throughput technologies of cancer genomics and proteomics, with large datasets, bioinformatics computation, artificial intelligence, and machine learning to accelerate the process of cancer early detection and biomarker discovery and validation.
- Identify/characterize factors for risk prediction or early detection of HNC, including nutrition, microbiome, immunocompetence, oral health, and health disparity.
While molecular biomarkers have been studied, there are major gaps in the systematic discovery and validation of these potential biomarkers for clinical use. The immediate benefit of AHEAD is the creation of an interdisciplinary group with diverse background to conduct cohesive collaboration targeted specifically for HNC early detection and prevention. Projects supported through this initiative are required to use validated, highly annotated (pathologic and clinical) biospecimen collections including longitudinal sampling, from human and preclinical experimental sources. In addition, our partnership with NCI offers AHEAD investigators access to valuable NCI resources to enhance their research capabilities as well as unique opportunities to interact with the Early Detection Research Network (EDRN), a national infrastructure funded to discover, develop, and validate biomarkers for risk assessment, detection, and molecular diagnosis and prognosis of early cancer.
Projects relevant to this concept are under-represented in NIDCR’s Oral and Salivary Cancer Biology portfolio. Between 2007-2018, NIDCR funded only two biomarker-based projects for screening and early detection. Since 2019, NIDCR increased the funding in this relevant area to four, two imaging-based and two biomarker-based studies through the publications of trans-NIH FOAs. NCI has reported three funded HNC projects relevant to this concept, over the past ten years. In 2021, NIDCR joined The Early Detection Research Network (EDRN): Biomarker Characterization Centers (RFA-CA-21-035) which included HNC.
- Hussein AA, et al. A review of the most promising biomarkers for early diagnosis and prognosis prediction of tongue squamous cell carcinoma. British J Cancer. 119:724-728 (2018).
- Chu HW, et al. Identification of salivary biomarkers for oral cancer detection with untargeted and targeted quantitative proteomics approaches. Mol Cell Proteomics. 18:1796-1806 (2019).
- Gooi Z, et al. The Epidemiology of the Human Papillomavirus Related to Oropharyngeal Head and Neck Cancer. Laryngoscope. 126(4):894-900 (2016).
- Alshafi E, et al (2019). Clinical update on head and neck cancer: molecular biology and ongoing challenges. Cell Death Dis. 10, 540 (2019).
- Denny JC, Collins FS. Precision medicine in 2030—seven ways to transform healthcare. Cell. 184(6):1415-1419 (2021).
- Sharpless N, Liang H, Hutter C, Zenklusen JC, Shen H, Giordano TJ. The TCGA Legacy. Cell. 173(2):281-282 (2018).
- National Cancer Institute Early Detection Research Network.
- NOT-DE-21-010: Notice of Special Interest (NOSI): Precision Imaging of Oral Lesions.
- NOT-CA-20-031: Notice of Special Interest (NOSI): Advancing Head and Neck Cancer Early Detection Research (AHEAD).
- PAR-20-155: Academic-Industrial Partnerships (AIP) to Translate and Validate In Vivo Imaging Systems (R01 Clinical Trial Optional).
- PAR-18-530: Academic-Industrial Partnerships for Translation of Technologies for Diagnosis and Treatment (R01 - Clinical Trial Optional).