Development and Profiling of Human-in-Mouse Models of Salivary Carcinomas

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DESCRIPTION (provided by applicant): Salivary carcinoma is a devastating disease whose primary treatment often relies on surgery. Cure rates are unacceptable and for patients that cannot be treated surgically due to tumor spread or patient characteristics, the chance of cure is very low. Very little is known about the molecular pathogenesis of these tumors and translational research is hampered by the lack of tools for studying salivary cancers. Targeted agents and individualized medicine may be the key for salivary cancer therapy, but identifying agents to which these tumors are responsive is very difficult using the standard clinical trial format. The expense of clinical trials, the limited number of salivary cancer patients who are eligible, and the expected moderate to low response rates for targeted agents suggest that development of new tools for pre-clinical testing to identify molecular characteristics within tumors that predict response would be useful. We propose to develop a low cost and tractable human-in-mouse model of primary salivary carcinoma. Techniques will develop and expand from our experience with creation of a human-in-mouse model of HNSCC that is based on short-term culture (1-5 days) followed by implantation into mice. One advantage of the proposed model is that primary tumors, not established cell lines, will be the source of the modeled tumors so that the genetic diversity of salivary carcinomas may be better represented. Another advantage is that before modeling, tumors can be engineered to express luciferase so that tumor growth and response can be easily monitored without animal sacrifice. The purpose of the proposed studies is to develop an in vivo salivary cancer model that can be used for molecular and cell biological studies and to serve as a tool for development of therapeutic agents. We will model tissue obtained through the Head and Neck Biospecimen Repository at the time of salivary cancer biopsy or resection. On average, twenty patients with salivary tumors are enrolled yearly in the Head and Neck Biospecimen Repository. In addition, a goal of this proposal is to determine gene expression profiles for adenoid cystic carcinoma, mucoepidermoid carcinoma and adenocarcinoma. Gene expression profiles will expand our understanding of the molecular characteristics of these salivary tumor types and will be used to validate the human-in-mouse model. Gene expression profiles will be created for primary salivary cancers and for derivative modeled tumors and along with histology and IHC will be used to determine if modeled tumors most closely resemble the parent tumor type from which they were derived. Development of a human-in-mouse model of primary salivary cancer will provide a tool that can be used in a pre-clinical setting to predict response to individual or combinations of targeted therapy. Characteristics of responding tumors from the human-in-mouse model could then be used to inform clinical trials so that patients with tumors most likely to respond would be enrolled. Development of a human-in-mouse animal model of salivary cancer will be a step toward development of effective therapy for these resistant tumors. PUBLIC HEALTH RELEVANCE: Little is known about the molecular pathology of salivary cancer and few tools exist for study of this uncommon cancer. We propose to determine gene expression profiles for the most common salivary cancers and to create a human-in-mouse model of salivary carcinomas using primary tumors as the starting material and based on a similar model that we have created for head and neck squamous cell carcinoma. A human-in-mouse model of salivary cancer will be a tool that can be used for drug development and for understanding molecular alterations in these tumors.