Mechanisms Regulating Reversal of Premalignancy and Threapuetic Sensitivity

癌前病变和治疗敏感性逆转的调节机制

• 批准号: 8534893
• 负责人: Priscilla A. Furth
• 金额: $ 19.39万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534893
• 关键词: Area; Benign; Cancer Histology; Carcinoma in Situ; Cell Culture Techniques; Cells; Cellular biology; Cessation of life; Chemosensitivity Assay; Clinical; Data; Development; Disease; Disseminated Malignant Neoplasm; Dysplasia; Epithelial; Epithelial Cells; Evaluation; Excision; Female; Formalin; Freezing; Functional disorder; Future; Genetically Engineered Mouse; Goals; Head and Neck Cancer; Hereditary Disease; Histologic; Histology; Human; Hyperplasia; In Vitro; Institutional Review Boards; Lead; Life; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of salivary gland; Metastatic Lesion; Metastatic/Recurrent; Methodology; Minor salivary gland structure; Molecular; Molecular Profiling; Mus; Normal tissue morphology; Oncogenes; Operative Surgical Procedures; Outcome; Parotid Gland; Pathogenesis; Physicians; Preclinical Testing; Preparation; Primary Cell Cultures; Protocols documentation; Radiation therapy; Research; Research Personnel; Resource Sharing; Salivary; Salivary Gland Neoplasms; Salivary Gland Tissue; Salivary Glands; Scientist; Specimen; Staging; Submandibular gland; Surgeon; System; Techniques; Technology; Testing; Therapeutic; Tissue Banking; Tissue Banks; Tissue Embedding; Tissue Sample; Tissues; Translating; Validation; Work; Xenograft Model; Xenograft procedure; cancer type; chemotherapy; comparative; cost effective; effective therapy; experience; human tissue; in vivo; innovation; male; mouse model; novel; research study; response; tissue culture; tumor; tumor progression

1 Our long-range research goal is to translate molecular definition of cancer pathophysiology into more 2 effective therapy. The project goal is development of relevant tissue culture and mouse models to study 3 pathogenesis of different histological types of salivary tumor and perform preclinical testing of potential 4 therapeutics. Specific aims: 1. Utilize an established conditional genetically engineered mouse model of 5 submandibular salivary cancer to further define molecular signatures at different stages of salivary gland 6 cancer progression and determine if disease-relevant molecular signatures and response to therapeutics in 7 vivo are maintained in two types of in vitro culture. 2. Use human tissue samples of parotid, submandibular and 8 minor salivary glands obtained from de-identified surgical specimens to establish a living bio-bank (a panel of 9 cell cultures) from normal, benign, invasive cancer and metastatic human salivary gland tissue using 10 conditional reprogramming to evaluate potential therapeutic response in vitro and in xenograft models and 11 establish molecular signatures of disease. The significance of the proposal is that it answers the stated FOA, 12 e.g. provide molecular signatures of salivary gland tumors and develop relevant mouse models to study 13 pathogenesis and perform preclinical testing. The major innovation in the project is the utilization of a novel 14 system for conditionally reprogramming normal, preneoplastic and malignant epithelial cells developed by 15 project co-investigators that permit us to readily generate human material representative of different cancer 16 types for determining molecular signatures and preclinical testing. We are relatively unique in that we already 17 have molecularly characterized a conditional mouse model of submandibular salivary gland cancer in which 18 expression of the initiating oncogene can be turned off to study molecular determinants of cancer progression 19 independent from the initiating oncogene. The methodology is a logical sequence of experiments utilizing 20 material from both mouse models and human primary disease material for determination of molecular 21 signatures and testing of potential therapeutics while evaluating a unique system for reprogramming epithelial 22 cells that can be used for expanding small numbers of primary cells and may have future clinical utility for 23 determining optimal therapies for uncommon cancers or otherwise challenging clinical cases. Expected 24 outcomes are an adequately powered test of the utility of conditionally reprogrammed cells for determining 25 response to potential therapeutics and molecular signature testing using a well-characterized mouse model 26 and establishment and evaluation of a panel cell cultures of different types of human salivary tumors for further 27 use in preclinical testing and determination of molecular signatures. The results will effect other research 28 areas by establishing caveats for the use of similar experimental approaches for the characterization (both 29 therapeutically and by molecular signature) of other epithelial cancer types and pave the way for cost-effective 30 and timely approaches for predicting in vivo chemotherapy sensitivity. 1

1我们的远程研究目标是将癌症病理生理学的分子定义转化为更多 2有效的疗法。项目目标是开发相关的组织培养和小鼠模型来研究 3不同组织学类型的唾液肿瘤的发病机制并对电势进行临床前测试 4种治疗学。具体目的：1。利用已建立的条件基因工程鼠标模型 5下颌下唾液腺癌，进一步定义唾液腺不同阶段的分子特征 6癌症进展，并确定与疾病相关的分子特征和对治疗剂的反应是 7个体内维持在两种类型的体外培养中。 2。使用人体组织样品，下颌下和 8个从去识别的手术标本中获得的小唾液腺建立生物银行（一个面板 9个细胞培养）使用正常，良性，侵入性癌和转移性人类唾液腺组织 10条件重编程，以评估体外和异种移植模型中的潜在治疗反应以及 11建立疾病的分子特征。该提案的意义在于它回答了陈述的FOA， 12，例如提供唾液腺肿瘤的分子特征，并开发相关的小鼠模型来研究 13发病机理并进行临床前测试。该项目的主要创新是使用小说 14通过有条件重新编程的正常，肿瘤和恶性上皮细胞的系统 15个项目共同投资者，使我们很容易产生不同癌症的人类材料 16种用于确定分子特征和临床前测试的类型。我们相对独特，因为我们已经 17分子表征了下颌下唾液腺癌的条件小鼠模型，其中 18启动癌基因的表达可以关闭以研究癌症进展的分子决定因素 19独立于发起癌基因。该方法是利用实验的逻辑序列 20来自小鼠模型和人类原发性疾病材料的材料，用于测定分子 21签名和潜在治疗学测试，同时评估用于重新编程的独特系统 22个可用于扩展少量原始细胞的细胞，并可能具有未来的临床实用性 23确定不常见癌症或其他挑战临床病例的最佳疗法。预期的 24个结果是有条件重编程单元的实用性的充分动力测试 25对潜在的治疗剂和使用特征良好的小鼠模型的反应 26以及对不同类型人类唾液肿瘤的面板细胞培养的建立和评估，以进一步 27用于临床前测试和分子特征的测定。结果将影响其他研究 通过建立使用相似的实验方法来进行表征的28个区域（两者都 29在治疗和分子签名中）的其他上皮癌类型，为具有成本效益的道路铺平了道路 30和及时预测体内化学疗法敏感性的方法。 1