The role of DCLK1 in the initiation of pancreatic ductal adenocarcinoma and colorectal cancer

DCLK1在胰腺导管腺癌和结直肠癌发生中的作用

• 批准号: 10472692
• 负责人: Dongfeng Qu
• 金额: $ 8.97万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472692
• 关键词: Cell Line; Cells; Cetuximab; Colon Carcinoma; Colorectal Cancer; Epidermal Growth Factor Receptor; Funding; Gefitinib; Genetically Engineered Mouse; Growth; KRAS2 gene; KRASG12D; Knock-in; Lead; Malignant neoplasm of pancreas; Mediating; Modeling; Molecular; Mutation; Neoplasm Metastasis; Oncogenic; Outcome Study; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phosphotransferases; Process; Proteomics; Research; Resistance; Role; Small Interfering RNA; Testing; Therapeutic; Up-Regulation; experimental study; in vitro Assay; innovation; knock-down; mutant; new therapeutic target; pancreatic ductal adenocarcinoma model; pancreatic tumorigenesis; stem cell biomarkers; targeted treatment; translational study; tumor; tumor xenograft

We recently demonstrated that doublecortin-like kinase 1 (DCLK1) is a putative colorectal and pancreatic cancer stem cell marker. 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. The DCLK1+ cell is now strongly implicated as a cell-of-origin for KRAS-driven pancreatic cancer, and recent proteomic studies demonstrate that knock-in of KRASG12/G13 mutations into CRC cells results in specific DCLK1 upregulation. Moreover, DCLK1 is highly expressed in CRC metastases and predicts significantly decreased survival in patients. The proposed studies for this application are related to two NCI-funded projects. 1. The role of DCLK1 in the initiation of pancreatic ductal adenocarcinoma. 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. 2. The role of DCLK1 in the initiation of colorectal cancer. We propose to unravel DCLK1's role in KRAS-mutant CRC progression and assess DCLK1-targeted therapies with the following Specific Aims: Aim 1: Determine the role of DCLK1 and the DCLK1+ tuft cell in the initiation and progression of KRAS-mutant colorectal cancer. Aim 2: Dissect DCLK1's mechanistic role in CRC downstream of KRASG12D and in the background of APC loss. Aim 3: Demonstrate the feasibility of targeting DCLK1 in KRAS-mutant patient-derived CRC models as a primary therapy and to overcome resistance to EGFR-targeted cetuximab and gefitinib. The current proposals include innovative genetically engineered mouse models of PDAC and CRC, innovative cell lines, and innovative concepts that may lead to translational studies on PDAC and CRC.

我们最近证明双皮质素样激酶 1 (DCLK1) 是一种假定的结直肠和 胰腺癌干细胞标志物。我们还证明了 DCLK1 可以调节多个 致癌和肿瘤支持途径和过程。此外，siRNA介导 DCLK1 敲低导致胰腺癌和结直肠癌肿瘤生长停滞 异种移植物。 DCLK1+ 细胞现在被强烈认为是 KRAS 驱动的细胞起源 胰腺癌，最近的蛋白质组学研究表明 KRASG12/G13 的敲入 CRC 细胞突变导致特定的 DCLK1 上调。此外，DCLK1 是高度 在 CRC 转移中表达并预测患者生存率显着下降。 本申请的拟议研究与两个 NCI 资助的项目相关。 1. DCLK1在胰腺导管腺癌发生中的作用。我们将测试我们的 通过实验提出的假设有以下三个具体目标： 目标 1：确定 Dclk1+ 细胞启动的功能和分子机制 胰腺肿瘤发生。 目标 2：描述 Dclk1 缺失在胰腺肿瘤发生中的多区室作用。 目标 3：证明 PDAC 中靶向 Dclk1 作为治疗方法的可行性。 2. DCLK1在结直肠癌发生中的作用。我们建议解开 DCLK1 的 KRAS 突变 CRC 进展中的作用并通过以下方法评估 DCLK1 靶向疗法 具体目标： 目标 1：确定 DCLK1 和 DCLK1+ 簇细胞在疾病发生和进展中的作用 KRAS 突变结直肠癌。 目标 2：剖析 DCLK1 在 KRASG12D 下游 CRC 和 APC损失的背景。 目标 3：证明在 KRAS 突变患者衍生的 CRC 中靶向 DCLK1 的可行性 模型作为主要疗法并克服对 EGFR 靶向西妥昔单抗的耐药性 吉非替尼。 目前的提案包括创新的 PDAC 基因工程小鼠模型和 CRC、创新细胞系和可能导致转化研究的创新概念 PDAC 和 CRC。