The role of DCLK1 in the initiation of pancreatic ductal adenocarcinoma

DCLK1在胰腺导管腺癌发生中的作用

基本信息

批准号：
9024478
负责人：
Courtney Wayne Houchen
金额：
$ 34.59万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
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：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9024478
关键词：
Ablation Agar Biological Assay Blinded Caerulein Cancer Etiology Cell Line Cells Cessation of life Characteristics Colorectal Cancer Data Development Diagnosis Dose Ductal Ductal Epithelial Cell Encapsulated Genetically Engineered Mouse Growth Histologic Histology Human Implant In Vitro Infection Inflammation Inflammatory Injury Intestines Investigation Isogenic transplantation Lead Light Link Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Messenger RNA Metaplasia Modeling Molecular Molecular Analysis Mus Mutation Neoplasm Metastasis Nodule Oncogenic Outcome Study Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatitis Pathway interactions Patients Pharmaceutical Preparations Phenocopy Phenotype Phosphotransferases Point Mutation Process Research Role Small Interfering RNA Solid Neoplasm Sorting - Cell Movement Staging Stem cells Survival Rate Target Populations Testing Therapeutic Tumor Cell Invasion Tumor Stem Cells United States Validation Xenograft procedure base cancer recurrence cancer stem cell clinically relevant epithelial to mesenchymal transition in vitro Assay in vivo innovation islet kinase inhibitor knock-down malignant breast neoplasm migration mouse model nanoparticle neoplastic neoplastic cell new therapeutic target novel therapeutics outcome forecast pancreatic cancer cells pancreatic neoplasm pancreatic tumorigenesis pluripotency preclinical study public health relevance radiation resistance research study self-renewal small hairpin RNA small molecule therapeutic target translational study tumor tumor growth tumor initiation tumor progression tumor xenograft tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any major malignancy with less than a 6% 5-year survival rate. It is one of the leading causes of cancer-related death in the developed world and is the fourth leading cause of cancer death in the United States. Patients with PDAC are often diagnosed at late stages with extensive local tumor invasion and early metastasis, presenting a major obstacle to all forms of therapy. Recently, cancer stem cells (CSCs) have come into focus as potential therapeutic targets in multiple cancers. The accumulation of mutations in CSCs enhances chemo/radiation resistance ablating the effect of therapy, leading to the cancer recurrence, characteristic of PDAC. Conversely, because CSCs are a unique subset of the tumor cell population, targeting these cells may lead to the identification of effective drugs for poorly treatable cancers such as PDAC. Epithelial-to-mesenchymal transition (EMT) is a well-documented characteristic of metastatic malignancies including PDAC. There is an increasing body of evidence linking EMT to a stem cell phenotype characterized by a capacity for self-renewal and differentiation, and expression of pluripotency factors. We recently demonstrated that doublecortin-like kinase 1 (DCLK1) is a putative pancreatic stem cell marker. DCLK1 is upregulated in several human solid tumor cancers, including colorectal, pancreatic, breast and prostate cancer. We also demonstrated that DCLK1 regulates multiple oncogenic and tumor supporting pathways and processes. Furthermore, siRNA mediated knockdown of DCLK1 results in growth arrest of pancreatic and colorectal cancer tumor xenografts. Moreover, introducing the KRASG12D mutation into Dclk1-positive cells in a Dclk1CreERT mouse model leads to rapid pancreatic cancer development synonymous to human PDAC. Recent studies also validated Dclk1 as a specific tumor stem cell marker in the pancreas and intestine. On the basis of these findings, our central hypothesis is that Dclk1 initiates and drives progression of PDAC and represents a viable therapeutic option worthy of investigation. We will test our hypotheses with the experiments proposed in the following three specific aims: Aim 1: To determine the functional and molecular mechanisms through which Dclk1+ cells initiate pancreatic tumorigenesis. Aim 2: To delineate the multi-compartmental role of Dclk1 deletion in pancreatic tumorigenesis. Aim 3: To demonstrate the feasibility of targeting Dclk1 in PDAC as a therapeutic approach. The current proposal includes innovative genetically engineered mouse models of PDAC, innovative cell lines, and innovative concepts that may lead to translational studies on PDAC.

描述（由适用提供）：胰腺导管腺癌（PDAC）的预后最差，任何主要恶性肿瘤的预后均低于6％的5年生存率。它是发达国家与癌症相关死亡的主要原因之一，并且是美国癌症死亡的第四个主要原因。 PDAC患者经常在晚期诊断出患有广泛的局部肿瘤侵袭和早期转移的患者，这是所有形式治疗的主要障碍。最近，癌症干细胞（CSC）已成为多种癌症的潜在治疗靶标。 CSC中突变的积累增强了化学/辐射耐药性消除治疗的作用，导致癌症复发，PDAC的特征。相反，由于CSC是肿瘤细胞群的独特子集，因此针对这些细胞可能会导致鉴定有效治疗的药物（例如PDAC）。上皮到间质转变（EMT）是包括PDAC在内的转移性恶性肿瘤的有据可查的特征。越来越多的证据将EMT与干细胞表型联系起来，其特征是自我更新和分化的能力以及多能因素的表达。我们最近证明了双铁蛋白样激酶1（DCLK1）是推定的胰腺干细胞标记。 DCLK1在几种人类实体瘤癌中进行了更新，包括结直肠癌，胰腺，乳腺癌和前列腺癌。我们还证明DCLK1调节多种致癌和肿瘤支持途径和过程。此外，siRNA介导的DCLK1敲低导致胰腺癌和结直肠癌肿瘤Xenographictics的生长停滞。此外，将KRASG12D突变引入DCLK1 Creert小鼠模型中的DCLK1阳性细胞中，导致胰腺癌的快速发展与人PDAC同义。最近的研究还将DCLK1验证为胰腺和肠中的特定肿瘤干细胞标记。根据这些发现，我们的中心假设是DCLK1启动并驱动PDAC的发展，代表了值得投资的可行治疗选择。我们将通过以下三个特定目的提出的实验来检验我们的假设：目标1：确定DCLK1+细胞启动胰腺肿瘤发生的功能和分子机制。目的2：描绘DCLK1缺失在胰腺肿瘤发生中的多隔间作用。目标3：证明将DCLK1靶向PDAC作为治疗方法的可行性。当前的建议包括创新的PDAC基因工程小鼠模型，创新的细胞系以及可能导致PDAC转化研究的创新概念。