Validated Modeling and Culture of Salivary Cancers

描述(申请人提供)：唾液癌是一组毁灭性的恶性肿瘤，几乎完全通过手术切除加或不加放射治疗。低发病率、多组织学、缺乏分子细节以及收集这些肿瘤的基础设施不足都是导致治疗选择相对匮乏的原因之一。我们认为，阻碍对涎腺癌的了解和治疗进步的最大障碍是缺乏或缺乏用于研究的有效的异种移植模型或细胞系。如果没有免费的异种移植或细胞系，机械性或临床前研究是不可能的。在这里，我们建议建立多种组织学的人涎腺癌的小鼠异种移植模型。我们已经移植了多种唾液腺类型，包括：腺样囊性癌、腺癌、多形性低级腺癌、癌外多形性腺瘤和涎腺导管癌。我们还建议使用原发肿瘤或小鼠异种移植瘤作为起始材料，从多种组织类型的唾液癌中创建细胞系。对于细胞系的发展，我们继续通过调整肿瘤分离方案、培养液、平板涂层和培养缺氧来优化我们的培养环境。通过进行这些调整，我们提高了多种涎癌类型来源的早期细胞培养的成功率，目前我们有活跃的早期传代细胞，来自未特殊说明的腺癌、多形性低级腺癌和癌前多形性腺瘤。一旦建立了异种移植和细胞系，将通过比较形态(异种移植)和基因表达(异种移植和细胞培养)来验证它们。我们拥有从手术切除中收集唾液癌的基础设施，并开发了用于短期培养和小鼠异种移植模型的肿瘤处理专业知识。我们将利用这些资源来创建和验证用于涎癌的小鼠异种移植模型和细胞系。这些经过验证的细胞系和异种移植瘤将是推进涎癌分子理解的关键，也是推进治疗所必需的。

DESCRIPTION (provided by applicant): Salivary cancers are a devastating group of malignancies treated almost exclusively by surgical excision with or without radiation. The low incidences, multiple histologies, lack of molecular details and inadequate infrastructure for collecting these tumors have each contributed to the relative paucity of treatment options. We suggest that the largest impediment blocking understanding of salivary cancers and advancement of therapy has been the lack or scarcity of validated xenograft models or cell lines for study. Without freely available xenografts or cell lines mechanistic or pre-clinical studies ar not possible. Here, we propose to create mouse xenograft models of human salivary cancers of multiple histologies. We have xenografted multiple salivary types including: adenoid cystic, adenocarcinoma not otherwise specified, polymorphous low grade adenocarcinoma, carcinoma ex-pleomorphic adenoma, and salivary ductal carcinoma. We also propose to create cell lines from multiple histological types of salivary cancer using primary tumors or murine xenografted tumors as starting material. For development of cell lines, we continue to optimize our culture environment with adjustment of tumor dissociation protocols, media, plate coatings, and culture hypoxia. By making these adjustments, we have increased our success of early cell culture derived from multiple salivary cancer types, and we currently have active early passages of cells derived from adenocarcinoma not otherwise specified, polymorphous low grade adenocarcinoma, and carcinoma ex-pleomorphic adenoma. Once xenografts and cell lines are created, they will be validated by comparison of morphology (xenografts) and gene expression (xenografts and cell cultures). We have the infrastructure for collection of salivary cancers from surgical resections and have developed expertise in processing of the tumors for short-term culture and murine xenograft modeling. We will leverage these resources to create and validate murine xenograft models and cell lines for salivary cancers. These validated cell lines and xenografted tumors will be critical to advance molecular understanding of salivary cancers and will be needed for advancement of therapy.