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Mouse Model for Human Pancreatic Ductal Adenocarcinoma

人胰腺导管腺癌小鼠模型

基本信息

批准号：
8249079
负责人：
Gloria Huei-Ting Su
金额：
$ 31.12万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8249079
关键词：
Alleles Apoptosis Cancer Model Cancer Patient Cancer cell line Cell Proliferation Data Development Drug Delivery Systems Drug Design EGF Signaling Pathway Engineering Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event Funding Future G1 Arrest Genes Genetic Genetically Engineered Mouse Histologic Histology Human In Vitro KRAS2 gene Knock-in Mouse Lead Lesion Ligands MADH4 gene Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metaplasia Modeling Mus Mutate Mutation Neoplasm Metastasis Oncogenes Oncogenic Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathway interactions Phenotype Premalignant Property Research Personnel Role Staging Stomach Tamoxifen Testing Therapeutic Transforming Growth Factor alpha Transgenes Tumor Suppressor Genes Work anticancer research base cancer cell cancer genetics cancer therapy design effective therapy functional restoration in vitro Assay in vivo insight mouse model mutant novel novel strategies overexpression pancreatic cancer cells pancreatic neoplasm pancreatic tumorigenesis prevent prospective public health relevance research study restoration senescence success therapeutic target tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The majority of human pancreatic cancer is presented as pancreatic ductal adenocarcinoma (PDA). Although we have increased our understanding of pancreatic cancer (PC) genetics in the past two decades, the 5-year survival of PC patients remains at 5%. Gaining a better understanding of metastasis and developing more effective treatments are two major challenges for pancreatic cancer researchers. Oncogene KRAS and tumor-suppressor genes p16 and SMAD4 are frequently mutated in human PDA. Our studies will focus on the roles of these 3 genes in pancreatic cancer progression and metastasis and their feasibility as drug targets. Based on the genetics of PDA, we have developed a mouse model that harbors an oncogenic Kras and inactivated p16 in the pancreases (p16/Kras/Pdx1 mice). We have shown that p16/Kras/Pdx1 mice develop mPanIN (precancerous lesions similar to those observed in humans), invasive cancer (similar to PDA), and metastasis at 100%. Our data demonstrate that p16 inactivation and Kras activation work synergistically in promoting pancreatic progression and metastasis, beyond early tumorigenesis. The continual participation of p16 and Kras in pancreatic cancer progression supports them as valid therapeutic targets. In addition, we also demonstrated progressive loss of the wild-type Kras allele is associated with metastasis in both mice and humans, suggesting that the wild-type Kras might have been selectively inactivated because it was inhibiting metastasis. In Aim 1, we will investigate if the wild-type Kras harbors tumor-suppressive functions by restoring or deleting the wild-type Kras allele in both human and murine pancreatic cancer cell lines and examine the impacts on cell proliferation and/or metastasis in vitro and in vivo. If wild-type Kras does have tumor- suppressive function, it would impact future drug design targeting Kras. In Aim 2 we propose to generate an inducible p16 knock-in mouse line (p16KI). The ability to induce p16 expression temporally during pancreatic tumorigenesis in p16/Kras/Pdx1 mice will allow us to evaluate if restoration of p16 is a feasible therapeutic strategy in vivo. Finally in Aim 3, we wish to continue our efforts of generating a new mouse model that does not involved an engineered oncogenic Kras allele. A portion of human PDA does not harbor KRAS mutations. We propose to continue our characterization of the Smad4lox/lox; P48Cre/+; MT-TGFalpha mice, which has shown promising development of mPanIN, which will likely progress to PDA. This model will enable us to understand pancreatic tumorigenesis that does not involve mutated KRAS and to test EGFR targeted therapies. As cancer treatments move toward target therapies, it is more important for us to understand the genes and the pathways that we design to target. In addition to further our understandings of the roles of KRAS, p16, and SMAD4 in pancreatic cancer progression and metastasis, the success of this application will impact how we design KRAS target therapies, provide new insights to p16 replacement/restoration therapies and EGFR inhibitor treatments, and offers new mouse models for human pancreatic cancer research. PUBLIC HEALTH RELEVANCE: Oncogene KRAS and tumor-suppressor genes p16 and SMAD4 are frequently mutated in human pancreatic cancer. Our studies will focus on the roles of these 3 genes in pancreatic cancer progression and metastasis and their feasibility as drug targets. These experiments will help us better understand the mechanism of metastasis and to develop more effective target therapies for pancreatic cancer patients.

描述（由申请方提供）：大多数人胰腺癌表现为胰腺导管腺癌（PDA）。尽管在过去的二十年里，我们对胰腺癌（PC）遗传学的了解有所增加，但PC患者的5年生存率仍为5%。更好地了解转移和开发更有效的治疗方法是胰腺癌研究人员面临的两大挑战。癌基因KRAS和肿瘤抑制基因p16和SMAD 4在人PDA中经常发生突变。我们的研究将重点关注这3个基因在胰腺癌进展和转移中的作用及其作为药物靶点的可行性。基于PDA的遗传学，我们已经开发了一种在胰腺中携带致癌Kras和失活p16的小鼠模型（p16/Kras/Pdx 1小鼠）。我们已经表明，p16/Kras/Pdx 1小鼠发生mPanIN（与人类中观察到的癌前病变相似），浸润性癌症（与PDA相似）和100%转移。我们的数据表明，p16失活和Kras激活协同作用，促进胰腺进展和转移，超越早期肿瘤发生。p16和Kras在胰腺癌进展中的持续参与支持它们作为有效的治疗靶点。此外，我们还证明野生型Kras等位基因的进行性丢失与小鼠和人类的转移有关，这表明野生型Kras可能因抑制转移而被选择性失活。在目的1中，我们将研究野生型Kras是否具有肿瘤抑制功能，通过恢复或删除人和小鼠胰腺癌细胞系中的野生型Kras等位基因，并检查体外和体内对细胞增殖和/或转移的影响。如果野生型Kras确实具有肿瘤抑制功能，则其将影响靶向Kras的未来药物设计。在目标2中，我们提出了一个诱导型p16基因敲入小鼠系（p16 KI）。在p16/Kras/Pdx 1小鼠胰腺肿瘤发生过程中暂时诱导p16表达的能力将使我们能够评估p16的恢复是否是一种可行的体内治疗策略。最后，在目标3中，我们希望继续努力产生不涉及工程致癌Kras等位基因的新小鼠模型。人PDA的一部分不具有KRAS突变。我们建议继续我们对Smad 4lox/lox; P48 Cre/+; MT-TGF α小鼠的表征，该小鼠已经显示出有希望的mPanIN的发展，其可能进展为PDA。该模型将使我们能够了解不涉及突变KRAS的胰腺肿瘤发生，并测试EGFR靶向治疗。随着癌症治疗向靶向治疗发展，对我们来说，了解我们设计的靶向基因和途径变得更加重要。除了进一步了解KRAS，p16和SMAD 4在胰腺癌进展和转移中的作用外，该应用的成功将影响我们如何设计KRAS靶向治疗，为p16替代/恢复治疗和EGFR抑制剂治疗提供新的见解，并为人类胰腺癌研究提供新的小鼠模型。公共卫生相关性：癌基因KRAS和肿瘤抑制基因p16和SMAD 4在人类胰腺癌中经常发生突变。我们的研究将重点关注这3个基因在胰腺癌进展和转移中的作用及其作为药物靶点的可行性。这些实验将有助于我们更好地了解胰腺癌的转移机制，并为胰腺癌患者开发更有效的靶向治疗方法。