The role of Dclk1 in the initiation of colorectal cancer

Dclk1在结直肠癌发生中的作用

基本信息

批准号：
10183185
负责人：
Courtney Wayne Houchen
金额：
$ 33.86万
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：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183185
关键词：
APC mutation Ablation Adenocarcinoma Adjuvant Adjuvant Therapy ApcMin/+ mice Biomedical Engineering Cancer Etiology Cancer Model Cell Line Cells Cessation of life Cetuximab Clustered Regularly Interspaced Short Palindromic Repeats Colon Colon Carcinoma Colorectal Cancer Data Diphtheria Toxin Disease Disease Progression Distant Dose Doxycycline Drug resistance Engraftment Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial FDA approved Gatekeeping Gefitinib Genes In Vitro Inflammation Inflammatory Injury Intestinal Neoplasms Intestines KRAS oncogenesis KRAS2 gene KRASG12D Knock-in Lead Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Mediating Mesenchymal Modeling Molecular Mus Mutation Neoplasm Metastasis Operative Surgical Procedures Organ Organoids Pancreas Patients Pharmaceutical Preparations Phosphotransferases Property Proteomics Resistance Role Signal Transduction Small Interfering RNA The Cancer Genome Atlas Therapeutic Therapeutic Agents Tumor Stem Cells Work adenoma advanced disease base cancer cell chemotherapy colon cancer cell line colon cancer patients colon tumorigenesis colorectal cancer metastasis colorectal cancer progression effective therapy in vivo kinase inhibitor knock-down mTOR Signaling Pathway metastatic colorectal mortality mouse model multidisciplinary mutant nanoparticle novel novel therapeutics patient derived xenograft model prevent response small hairpin RNA stem cells targeted treatment therapeutic target tumor tumor growth tumorigenesis tumorigenic

项目摘要

Colorectal cancer (CRC) is the 3rd leading cause of cancer death in the U.S, and it is a necessity to develop better drugs for those with advanced disease. Specific markers of CRC tumor stem cells (TSCs) have been elusive for many years, but recently strong data has emerged to support the TSC-role originally proposed by our lab for doublecortin-like kinase 1 (DCLK1) in APC mutant CRC. Specifically, Dclk1+ tuft cells initiate tumorigenesis in response to Apc mutation as demonstrated by lineage tracing in the ApcMin/+ model of intestinal neoplasia as well as in a model of inflammation-induced colon cancer. Strikingly, in the ApcMin/+ model, diphtheria toxin-inducible deletion of Dclk1+ cells results in a complete collapse of tumors with no apparent negative effects. While, APC is considered a gatekeeper in colorectal tumorigenesis and inactivating mutations exist in 34-70% of CRC tumors, KRAS mutations are also exceptionally common (30-60%) and associated with significantly decreased overall survival, particularly in metastatic disease. In addition to limiting therapeutic options for CRC patients, KRAS mutations accompanied by APC loss strongly increase tumorigenesis, metastasis, and TSC properties. 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 upregulation20. Moreover, DCLK1 is highly expressed in CRC metastases and predicts significantly decreased survival in patients. 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. These studies will utilize novel models to provide the first definitive assessment of the DCLK1's functional significance in KRAS-driven CRC and its potential as both a primary therapeutic target and an adjuvant to reverse KRAS-mediated resistance to EGFR inhibitors. We will pursue these studies with a highly multi- disciplinary team of experts including: Courtney Houchen and Dongfeng Qu (DCLK1/gastrointestinal cancers), Timothy Wang (DCLK1 mouse model), Channing Der (KRAS), Robert Langer (bioengineering), Hans Clevers (CRC organoids), Min Li (mouse surgery models), and Magdalena Bieniasz (patient-derived xenografts). These studies may lead to novel and effective therapies for patients with advanced CRC.

结直肠癌（CRC）是美国癌症死亡的第三主要原因，这是必要的为患有晚期疾病的人开发更好的药物。 CRC肿瘤干细胞的特定标记（TSC）具有多年以来一直难以捉摸，但是最近出现了强大的数据来支持最初提出的TSC角色通过我们的APC突变体CRC中的DoubleCortin样激酶1（DCLK1）的实验室。具体而言，DCLK1+簇细胞启动肿瘤发生对APC突变的响应，如在APCMIN/+模型中的谱系跟踪所证明的肠道肿瘤以及炎症诱导的结肠癌模型。令人惊讶的是，在apcmin/+中模型，DCLK1+细胞的白喉毒素可诱导的缺失导致肿瘤完全崩溃，无明显的负面影响。而APC被认为是结直肠肿瘤发生和灭活突变的守门人在CRC肿瘤中，KRAS突变也非常普遍（30-60％），并且与总体生存率显着降低，特别是在转移性疾病中。除了限制治疗 CRC患者的选择，伴随APC损失的KRAS突变大大增加了肿瘤发生，转移和TSC特性。现在，DCLK1+细胞被强烈牵涉到Kras-的原始细胞驱动的胰腺癌和最近的蛋白质组学研究表明，KRASG12/G13突变的敲击进入CRC细胞会导致特定的DCLK1上调20。此外，DCLK1在CRC中高度表达转移和预测患者的存活率显着降低。我们建议解散DCLK1在 KRAS突变的CRC进展并评估以下特定目的： AIM 1：确定DCLK1和DCLK1+ Tuft细胞在KRAS突变的启动和进展中的作用结直肠癌。 AIM 2：剖析DCLK1在KRASG12D和APC背景的CRC中的机械作用损失。 AIM 3：证明将DCLK1靶向KRAS突变患者衍生的CRC模型的可行性初级疗法并克服对EGFR靶向的西妥昔单抗和吉非替尼的抵抗力。这些研究将利用新型模型来提供对DCLK1功能的首次确定评估 KRAS驱动的CRC的重要性及其作为主要治疗靶点的潜力，又是对反向KRAS介导的对EGFR抑制剂的抗性。我们将通过高度多的纪律专家团队，包括：考特尼·侯顿（Courtney Houchen）和东芬（Dongfeng Qu）（DCLK1/胃肠道癌）， Timothy Wang（DCLK1鼠标模型），Channing der（KRAS），Robert Langer（Bio Ginesgineering），Hans Clevers （CRC类器官），Min Li（小鼠手术模型）和Magdalena Bieniasz（患者衍生的异种移植物）。这些研究可能会导致晚期CRC患者的新型和有效的疗法。