The role of Dclk1 in the initiation of colorectal cancer

Dclk1在结直肠癌发生中的作用

• 批准号: 9392671
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9392671
• 关键词: Ablation; Adenocarcinoma; Adjuvant; Adjuvant Therapy; Alpha Cell; 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; KRAS2 gene; Knock-in; Lead; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mediating; Mesenchymal; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Organ; Organoids; PIK3CG gene; Pancreas; Patients; Pharmaceutical Preparations; Phosphotransferases; Property; Proteomics; Resistance; Role; Signal Transduction; Small Interfering RNA; Stem cells; The Cancer Genome Atlas; Therapeutic; Therapeutic Agents; Tumor Stem Cells; Tumorigenicity; Work; Xenograft procedure; adenoma; advanced disease; base; cancer cell; chemotherapy; colon cancer cell line; colon cancer patients; colon tumorigenesis; effective therapy; in vivo; kinase inhibitor; knock-down; mTOR Signaling Pathway; metastatic colorectal; mortality; mouse model; multidisciplinary; mutant; nanoparticle; novel; novel therapeutics; prevent; response; small hairpin RNA; targeted treatment; therapeutic target; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

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大原因，因此有必要 为晚期疾病患者开发更好的药物。 CRC 肿瘤干细胞 (TSC) 的特异性标记物 多年来一直难以捉摸，但最近出现了强有力的数据来支持最初提出的 TSC 角色 由我们实验室在 APC 突变型 CRC 中检测双皮质素样激酶 1 (DCLK1)。具体来说，Dclk1+簇细胞启动 ApcMin/+ 模型中的谱系追踪证实了 Apc 突变引起的肿瘤发生 肠道肿瘤以及炎症诱导的结肠癌模型。引人注目的是，在 ApcMin/+ 中 模型中，白喉毒素诱导的 Dclk1+ 细胞缺失导致肿瘤完全崩溃，且没有 明显的负面影响。 而APC被认为是结直肠肿瘤发生的看门人，失活突变存在于34-70% 在 CRC 肿瘤中，KRAS 突变也异常常见 (30-60%)，并且与 显着降低总体生存率，特别是在转移性疾病中。除了限制治疗外 CRC 患者的选择，伴随 APC 缺失的 KRAS 突变强烈增加肿瘤发生， 转移和 TSC 特性。 DCLK1+ 细胞现在被强烈认为是 KRAS- 的起源细胞。 驱动胰腺癌，最近的蛋白质组学研究表明 KRASG12/G13 突变的敲入 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 转移并预测患者的生存率显着下降。我们建议阐明 DCLK1 在以下方面的作用： KRAS 突变 CRC 进展并评估 DCLK1 靶向疗法，具体目标如下： 目标 1：确定 DCLK1 和 DCLK1+ 簇细胞在 KRAS 突变体的起始和进展中的作用 结直肠癌。 目标 2：剖析 DCLK1 在 KRASG12D 下游的 CRC 和 APC 背景中的机制作用 损失。 目标 3：证明在 KRAS 突变患者衍生的 CRC 模型中以 DCLK1 为目标的可行性 主要治疗并克服对 EGFR 靶向西妥昔单抗和吉非替尼的耐药性。 这些研究将利用新颖的模型对 DCLK1 的功能提供首次明确的评估 KRAS 驱动的 CRC 中的重要性及其作为主要治疗靶点和辅助治疗的潜力 逆转 KRAS 介导的 EGFR 抑制剂耐药性。我们将以高度多元化的方式开展这些研究 学科专家团队包括：Courtney Houchen 和 Dongfeng Qu（DCLK1/胃肠道癌症）， Timothy Wang（DCLK1 小鼠模型）、Channing Der (KRAS)、Robert Langer（生物工程）、Hans Clevers （CRC 类器官）、Min Li（小鼠手术模型）和 Magdalena Bieniasz（患者来源的异种移植物）。 这些研究可能会为晚期结直肠癌患者带来新颖有效的治疗方法。