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

描述(申请人提供)：涎癌是一种毁灭性的疾病，其主要治疗通常依赖于手术。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，治愈的机会非常低。人们对这些肿瘤的分子发病机制知之甚少，由于缺乏研究唾液癌的工具，翻译研究受到阻碍。靶向药物和个体化药物可能是唾液癌治疗的关键，但使用标准的临床试验形式很难确定这些肿瘤对哪些药物有反应。临床试验的费用，符合条件的唾液癌患者的有限数量，以及靶向药物预期的中低应答率表明，开发新的临床前测试工具以确定肿瘤内预测反应的分子特征将是有用的。我们建议建立一种低成本、易处理的人在鼠原发涎腺癌模型。技术将在我们的经验基础上发展和扩展，建立人在小鼠体内的HNSCC模型，该模型基于短期培养(1-5天)，然后移植到小鼠体内。提出的模型的一个优点是，原发肿瘤，而不是已建立的细胞系，将是建模肿瘤的来源，以便更好地代表唾液腺癌的遗传多样性。另一个优点是，在建模之前，肿瘤可以被设计成表达荧光素酶，这样就可以很容易地监测肿瘤的生长和反应，而不需要牺牲动物。这项研究的目的是开发一种可用于分子和细胞生物学研究的体内唾液癌模型，并作为开发治疗药物的工具。我们将在涎癌活检或切除时对通过头颈部生物样本资料库获得的组织进行建模。平均每年有20名唾液肿瘤患者在头颈生物医学资料库登记。此外，这项建议的一个目标是确定腺样囊性癌、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的分子特征的理解，并将用于验证人在小鼠中的模型。将为原发唾液癌和衍生模型肿瘤以及组织学和IHC创建基因表达谱，以确定模型肿瘤是否与它们衍生的亲代肿瘤类型最相似。人在鼠的原发唾液癌模型的开发将提供一种工具，可以在临床前环境中使用，以预测对个别或联合靶向治疗的反应。然后，可以使用人在小鼠模型中对肿瘤有反应的特征来为临床试验提供信息，以便招募最有可能有反应的肿瘤患者。发展唾液腺癌的人鼠动物模型将是朝着开发这些耐药肿瘤的有效治疗方法迈出的一步。 公共卫生相关性：人们对唾液癌的分子病理学知之甚少，研究这种罕见癌症的工具也很少。我们建议确定最常见的唾液癌的基因表达谱，并以原发肿瘤为起始材料，基于我们为头颈部鳞状细胞癌创建的类似模型，创建唾液腺癌的人-鼠模型。唾液腺癌的人鼠模型将成为一种工具，可以用于药物开发和了解这些肿瘤的分子变化。

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.