Mechanisms Regulating Reversal of Premalignancy and Threapuetic Sensitivity

1我们的长期研究目标是将癌症病理生理学的分子定义转化为更多 2有效治疗。项目目标是发展相关的组织培养和小鼠模型进行研究 3不同组织学类型的涎腺肿瘤的发病机制并进行潜在的临床前试验 4治疗方法具体目标：1.利用已建立的条件遗传工程小鼠模型， 5下颌下唾液腺癌，以进一步确定唾液腺不同阶段的分子特征 6癌症进展，并确定是否与疾病相关的分子特征和对治疗剂的反应， 7个活体细胞维持在两种类型的体外培养中。2.使用腮腺、下颌下和 8个小唾液腺，从去识别的外科标本中获得，以建立活生物库（一组 9细胞培养物）从正常、良性、侵袭性癌和转移性人唾液腺组织中， 10条件性重编程，以评估体外和异种移植模型中的潜在治疗反应， 11建立疾病的分子特征。该提案的重要性在于它回答了所述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进行研究 13发病机理并进行临床前试验。该项目的主要创新是利用了一本小说 14由以下开发的用于有条件地重编程正常、癌前和恶性上皮细胞的系统： 15个项目共同研究者，使我们能够容易地产生代表不同癌症的人体材料 16种类型用于确定分子特征和临床前测试。我们的独特之处在于 17人对下颌下唾液腺癌的条件性小鼠模型进行了分子表征，其中 18可以关闭起始癌基因的表达来研究癌症进展的分子决定因素 19独立于起始癌基因。该方法是一个逻辑顺序的实验，利用 来自小鼠模型和人原发性疾病材料的材料用于测定分子生物学活性。 21个签名和潜在疗法的测试，同时评估一个独特的系统，用于重新编程上皮细胞 22个细胞，其可用于扩增少量原代细胞，并且可能具有未来的临床实用性， 23为罕见癌症或其他具有挑战性的临床病例确定最佳疗法。预计 24个结果是对条件性重编程细胞用于确定 使用充分表征的小鼠模型对潜在治疗剂的反应和分子特征测试 26和建立和评估不同类型的人涎腺肿瘤的细胞培养物组，用于进一步的研究。 用于临床前测试和分子特征的测定。结果将影响其他研究 28个领域，通过建立使用类似的实验方法进行表征的警告（两者 29治疗和分子签名）的其他上皮癌类型，并铺平了道路，成本效益 30种预测体内化疗敏感性的及时方法。 1

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