Musashi-mediated control of pancreatic cancer growth and progression

武藏介导的胰腺癌生长和进展控制

基本信息

批准号：
9210060
负责人：
ANDREW M LOWY
金额：
$ 37.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9210060
关键词：
Cancer Etiology Cell Line Cells Cessation of life Data Development Disease Disease model Genetic Genetic Engineering Genetically Engineered Mouse Growth Growth and Development function Hematologic Neoplasms Heterogeneity Human Impairment In Vitro KRAS2 gene Knock-in Mouse Knockout Mice Malignant neoplasm of pancreas Mediating Modeling Mus Mutation Nature Neoplasm Metastasis Oncogenic Patients Pattern Primary Neoplasm Recurrence Reporter Role Sampling Signal Transduction Site Somatic Mutation Stem cells Subfamily lentivirinae Systemic Therapy TP53 gene Testing United States Work Xenograft procedure cancer initiation cancer stem cell cancer therapy genetic approach in vivo in vivo Model mouse model new therapeutic target novel pancreatic cancer cells pancreatic neoplasm public health relevance small hairpin RNA stem cell fate targeted treatment therapeutic target tool tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is now the 4th leading cause of cancer death in the United States. Despite some recent advances in systemic therapy, survival remains dismal in large part due to the aggressive nature of this disease and its propensity for early metastasis. Thus, there is a critical need to define new therapeutic targets that can more effectively block tumor growth and spread. To define new ways to approach cancer therapy we have focused on stem cell signals that are hijacked to drive cancer initiation, propagation, and recurrence. Using this approach we previously identified the stem cell fate determinant Musashi (Msi) as critically required for progression of hematologic malignancies. Importantly, we have recently found that Msi is highly expressed in pancreatic cancer cells in both mouse models of the disease and in primary patient samples. Further, our preliminary studies indicate that Msi inhibition functionally blocks the growth of pancreatic cancer cell lines as well as patient samples in vitro and in xenografts. These data have led us to hypothesize that pancreatic cancer growth and propagation is critically dependent on Msi. We will test this by determining 1) whether Msi expression marks "cancer stem cells", cells with preferential capacity for pancreatic cancer cell propagation, 2) whether Msi is necessary for propagation of pancreatic cancer in genetically engineered mouse models, and 3) whether Msi is necessary for human pancreatic cancer propagation in primary patient-derived xenografts. These studies will help define whether Msi is a key regulator of pancreatic cancer and if it may be an effective target for therapy.

描述（由申请人提供）：胰腺癌现在是美国癌症死亡的第四个主要原因。尽管在全身疗法方面取得了最新进展，但由于这种疾病的侵略性及其对早期转移的倾向，生存仍然很沮丧。因此，迫切需要定义可以更有效地阻断肿瘤生长和扩散的新治疗靶标。为了定义接受癌症治疗的新方法，我们专注于被劫持以驱动癌症开始，传播和复发的干细胞信号。使用这种方法，我们先前将干细胞命运决定性穆萨什（MSI）确定为血液学恶性肿瘤进展至关重要的。重要的是，我们最近发现，在疾病的小鼠模型和原发性患者样品中，MSI在胰腺癌细胞中高度表达。此外，我们的初步研究表明，MSI抑制在功能上阻止了胰腺癌细胞系的生长以及体外和异种移植物中的患者样本。这些数据使我们假设胰腺癌的生长和繁殖取决于MSI。我们将通过确定1）MSI表达来测试这一点，MSI表达是否标记了胰腺癌细胞传播的优先能力的细胞，2）2）MSI是否对于遗传性工程小鼠模型中胰腺癌的传播是否是必需的，以及3）MSI是否对于初级患者癌症中的人类胰腺癌传播是必需的。这些研究将有助于定义MSI是否是胰腺癌的关键调节剂，并且是否可能是治疗的有效靶标。