Mechanisms Regulating Reversal of Premalignancy and Threapuetic Sensitivity

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。本项目的目标是开展相关的组织培养和小鼠模型研究 3涎腺肿瘤不同组织学类型的发病机制及潜在的临床前检测 4治疗学。具体目标：1.利用已建立的条件基因工程小鼠模型 5颌下腺癌进一步确定涎腺不同阶段的分子特征 6癌症进展，并确定疾病相关的分子特征和对治疗的反应 7活体分别在两种类型的体外培养中保持。2.使用人的腮腺、下颌下和 8个从已确认身份的手术标本中获得的小唾液腺，以建立一个活生物库(一个小组 9细胞培养)从正常、良性、浸润性癌和转移性涎腺组织中提取 10条件重编程以评估在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。该提案的意义在于，它回答了所述的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进行研究 13发病机制，并进行临床前试验。该项目的主要创新是利用了一种新的 14对正常、癌前和恶性上皮细胞进行有条件重编程的系统 15个项目合作研究人员，使我们能够容易地产生代表不同癌症的人类材料 用于确定分子特征和临床前试验的16种类型。我们是相对独特的，因为我们已经 17已经对颌下腺癌的条件小鼠模型进行了分子表征，其中 可以关闭启动癌基因的表达来研究癌症进展的分子决定因素 19不依赖于启动癌基因。方法论是一系列符合逻辑的实验，利用 20种小鼠模型和人类原发病材料用于分子检测 21个潜在疗法的签名和测试，同时评估重新编程上皮细胞的独特系统 22细胞，可用于扩增少量的原代细胞，并可能具有未来的临床用途 23确定罕见癌症的最佳治疗方法或以其他方式挑战临床病例。预期 24个结果是对条件重新编程细胞的效用的充分动力测试，以确定 25使用特征明确的小鼠模型对潜在疗法和分子签名测试的反应 26人不同类型涎腺肿瘤细胞培养体系的建立和评价 27用于临床前试验和分子特征测定。这一结果将影响其他研究 28个领域，为使用类似的实验方法确定特征(两者 29治疗和分子标记)的其他上皮性癌类型，并铺平了成本效益的道路 30和及时预测体内化疗敏感性的方法。 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