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

描述（由申请人提供）：唾液癌是一种毁灭性的疾病，其主要治疗往往依赖于手术。治愈率是不可接受的，对于由于肿瘤扩散或患者特征而无法手术治疗的患者，治愈率非常低。对这些肿瘤的分子发病机制知之甚少，并且由于缺乏研究唾液癌的工具，转化研究受到阻碍。靶向药物和个体化药物可能是涎腺癌治疗的关键，但使用标准的临床试验形式来确定这些肿瘤对哪些药物有反应是非常困难的。临床试验的费用，符合条件的涎腺癌患者数量有限，预期靶向药物的中低反应率表明，开发用于临床前测试的新工具来识别肿瘤内预测反应的分子特征将是有用的。我们建议开发一种低成本、易于处理的人鼠原发性涎腺癌模型。技术将根据我们建立HNSCC人鼠模型的经验得到发展和扩展，该模型基于短期培养（1-5天），然后植入小鼠。该模型的一个优点是，原发肿瘤，而不是已建立的细胞系，将是模型肿瘤的来源，因此唾液癌的遗传多样性可能更好地代表。另一个优点是，在建模之前，可以设计肿瘤来表达荧光素酶，这样就可以很容易地监测肿瘤的生长和反应，而无需牺牲动物。本研究的目的是建立一个体内涎腺癌模型，该模型可用于分子和细胞生物学研究，并作为开发治疗药物的工具。我们将模拟在涎腺癌活检或切除时通过头颈部生物标本库获得的组织。平均每年有20例涎腺肿瘤患者被纳入头颈部生物标本库。此外，本研究的目的是确定腺样囊性癌、粘液表皮样癌和腺癌的基因表达谱。基因表达谱将扩大我们对这些唾液肿瘤类型分子特征的理解，并将用于验证人鼠模型。基因表达谱将用于原发性涎腺癌和衍生模型肿瘤，并与组织学和免疫组化一起用于确定模型肿瘤是否最接近其衍生的母肿瘤类型。原发性涎腺癌人鼠模型的开发将提供一种工具，可用于临床前环境，以预测对单个或联合靶向治疗的反应。然后，人鼠模型中产生反应的肿瘤的特征可以用于临床试验，这样最有可能产生反应的肿瘤患者就会被招募进来。人类-小鼠涎腺癌动物模型的开发将是开发有效治疗这些耐药肿瘤的一步。

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.