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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(申请人提供)：胰腺癌现在是美国癌症死亡的第四大原因。尽管最近在系统治疗方面取得了一些进展，但存活率仍然很低，这在很大程度上是由于这种疾病的侵袭性及其早期转移的倾向。因此，迫切需要定义新的治疗靶点，以更有效地阻止肿瘤的生长和扩散。为了定义癌症治疗的新方法，我们将重点放在干细胞信号上，这些信号被劫持来驱动癌症的启动、传播和复发。使用这种方法，我们以前发现干细胞命运决定因素武藏(MSI)对于血液系统恶性疾病的进展至关重要。重要的是，我们最近发现MSI在胰腺癌细胞中高度表达，在这种疾病的小鼠模型和原始患者样本中都是如此。此外，我们的初步研究表明，MSI抑制在体外和异种移植瘤中对胰腺癌细胞系和患者样本的生长具有抑制作用。这些数据使我们假设胰腺癌的生长和扩散严重依赖于MSI。我们将通过确定1)MSI表达是否标记“癌症干细胞”，即具有优先胰腺癌细胞增殖能力的细胞，2)MSI是否是胰腺癌在基因工程小鼠模型中生长所必需的，以及3)MSI是否是人类胰腺癌在原发患者来源的异种移植中生长所必需的，来测试这一点。这些研究将有助于确定MSI是否是胰腺癌的关键调节因子，以及它是否可能是有效的治疗靶点。