Salivary gland tumors constitute 1-6% of head and neck tumors numbering 3600 new cases per year inthe US. Though rare, there are 37 histopathological malignant subtypes and 13 benign subtypes of salivarygland tumors, making it one of the most challenging tumors to diagnose. While surgery is the main modality oftreatment, advance unresectable primary, recurrent and metastatic tumors are generally fatal. The rarity of thetumors and multiple histopathological subtypes generated major clinical challenges for the early detection,diagnosis, therapeutic interventions and prognosis of patients with salivary gland tumors. This application addresses the missing gaps in salivary gland tumor research by advancing the basicand translational sciences. Our approach is to perform comprehensive molecular characterization of salivarygland tumors using the most advanced omics technologies coupled with advanced data and bioinformaticsanalysis to develop tissue-based biomarkers for salivary gland malignancy detection as well as the potentialuse of salivary biomarkers to screen/risk assess symptomatic patients for salivary gland malignancies. Inadditional a systems network analysis approach (Weighted-Gene Co-Expression Network Analysis, WGCNA)will be use to examine the derived omics databases to identify pivotal molecular pathways and gene targets forsalivary gland malignancy development. Collective these approaches will lead to translational and mechanisticinsights for salivary tumor development that can be further translated for clinical applications as well asmechanistic evaluations using rodent models for salivary gland carcinogenesis.
Six Specific Aims are in place to test the hypothesis in this application.
Aim 1 is to procure fresh frozenmalignant and benign parotid gland tissues from the UCLA Head & Neck Oncology Clinic.
Aim 2 is to performcomprehensive profiling of parotid gland tumors' transcriptome; microRNA and epigenome using mostadvanced RNA sequencing and methylomics arrays.
Aim 3 will perform statistical and bioinformatics analysisfor the omics databases to select candidate biomarkers that can detect parotid gland malignancies. Thesecandidate biomarkers will be pre-validated in Aim 4 in an independent cohort of parotid gland malignant andbenign tumors.
Aim 5 is to explore the hypothesis that tissue-based dysregulated biomarkers in malignantparotid glands are concordantly dysregulated in saliva of these patients. Finally Aim 6 is a systems networkbased analysis of the omics databases to identify critical biological pathways and gene targets that are pivotalin the development of parotid gland malignancies. These pathway and targets outcome can be evaluated infuture mechanistic studies in salivary gland malignancy development by rodent models or cell lines. Our multidisciplinary research team has the expertise and track record to carry out the proposedmolecular characterization of parotid gland tumors as well as expertise to carryout the mechanistic andtranslational next steps to fully materialize the goals of this RFA.

Public Health Relevance

to Public Health Statement Salivary gland tumors are rare. However, they are aggressive and fatal. Due to its rarity (1-6% of head and neck cancers) and the fact that there are 24 variants of salivary gland cancers and 13 variants of benign subtypes, clinical diagnosis of salivary gland tumor is one of the worst, hampering treatment decisions and prognostics outcomes of patients. This application takes the novel and impactful approach to generate the most comprehensive molecular profile of salivary gland tumors to develop molecular signatures of salivary gland malignancies, saliva based biomarkers for early detection of salivary gland cancers and informatics outcomes that will identify critical biological pathways and gene targets that are involved in the mechanistic development of salivary gland malignancies. The outcomes of this application are molecular signatures of parotid gland cancer to assist clinical diagnosis;salivary biomarkers to assist early detection of salivary gland cancers and identified biological pathways and gene targets for mechanistic evaluation in rodent models for salivary gland tumor carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56DE023241-01
Application #
8534892
Study Section
Special Emphasis Panel (ZDE1-JR (18))
Program Officer
Venkatachalam, Sundaresan
Project Start
2012-09-07
Project End
2014-08-31
Budget Start
2012-09-07
Budget End
2014-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$211,387
Indirect Cost
$74,123
Name
University of California Los Angeles
Department
Dentistry
Type
Schools of Dentistry
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Zhang, Yong; Sun, Jie; Lin, Chien-Chung et al. (2016) The emerging landscape of salivary diagnostics. Periodontol 2000 70:38-52
Wong, David T W (2015) Salivary extracellular noncoding RNA: emerging biomarkers for molecular diagnostics. Clin Ther 37:540-51
Yakob, Maha; Fuentes, Laurel; Wang, Marilene B et al. (2014) Salivary biomarkers for detection of oral squamous cell carcinoma - current state and recent advances. Curr Oral Health Rep 1:133-141
Zhang, Yong; Sun, Jie; Lin, Chien-Chung et al. (2014) The emerging landscape of salivary diagnostics. Oral Health Dent Manag 13:200-10
Matse, Johannes H; Yoshizawa, Janice; Wang, Xiaoyan et al. (2013) Discovery and prevalidation of salivary extracellular microRNA biomarkers panel for the noninvasive detection of benign and malignant parotid gland tumors. Clin Cancer Res 19:3032-8