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Novel Dual Notch/PXR Targeting for Colon Cancer Therapy

用于结肠癌治疗的新型双Notch/PXR靶向

基本信息

批准号：
9198492
负责人：
Shrikant Anant
金额：
$ 68.87万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198492
关键词：
Adverse drug effect ApcMin/+ mice Architecture Binding Binding Sites Biological Availability Biological Markers Calmodulin Cancer Etiology Cell Death Cell Maintenance Cells Cessation of life Clinical Research Clinical Trials Colon Carcinoma Data Dimensions Dose Drug Industry Drug Kinetics Drug resistance Drug toxicity Endothelial Cells Epithelial Cells Fibroblasts Fluorouracil Future Gene Activation Goals Growth HCT116 Cells In Vitro Inbred BALB C Mice Mediating Methods MicroRNAs Modeling Morbidity - disease rate Mus Neoplasm Metastasis Notch Signaling Pathway Oral Oral Administration Pathway interactions Pharmaceutical Preparations Pharmacodynamics Phosphorylation Phosphotransferases Proteins Receptor Activation Receptor Gene Regimen Research Resistance development Role Signal Transduction Spleen Stem cells System Therapeutic Therapeutic Agents Toxic effect Trans-Activators Treatment Efficacy United States Water Woman Xenograft procedure analog base cancer cell cancer therapy cell type chemotherapeutic agent cis acting element colon growth efficacy study experimental study in vivo intravenous administration killings men mortality mouse model new therapeutic target notch protein novel novel marker novel therapeutic intervention novel therapeutics pharmacodynamic biomarker pre-clinical preclinical safety preclinical study pregnane X receptor prevent promoter public health relevance receptor expression targeted treatment treatment strategy tumor tumor microenvironment tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Colon cancer remains a leading cause of cancer related morbidity and mortality, both in the US and around the world. Many therapeutic agents and their combinations are being used to inhibit the growth and metastasis of the tumor. However, a couple of significant problems with these strategies are the development of resistance to the drugs and the increased side effects of the drugs. A critical reason for the drug resistance is that directly or indirectly targeted therapeutics through various kinase pathways, they activate the pregnane X receptor (PXR). Hence, novel targeted therapeutics is essential that suppress specific pathways but do not induce PXR. In this regard, we have developed a novel drug MRLTHB and water-soluble analog MRLTHBCD, which inhibits Notch-1 signaling and does not induce PXR. The goal of the current project is to further characterize the drug and generate preclinical data as an oral therapeutic both alone and in combination with 5-fluorouracil (5-FU) for colon cancer. In previous studies, we have determined that downregulating Doublecortin calmodulin-like kinase 1 (DCLK1) suppresses colon cancer xenograft growth, suggesting that targeting DCLK1 would be an efficient strategy for colon cancers. We have now determined that THB and THBCD specifically inhibit DCLK1 kinase activity and but do not affect the kinase activity calmodulin like kinases CAMKII and CAMKIV. In addition, we have determined that the compounds inhibit the growth of colon cancer cells in a novel culture method that we have developed termed "Tumor in a Dish" (TiD) where cancer cells are grown in a three-dimensional culture that includes normal epithelial cells, fibroblasts and endothelial cell. The model creates an in vivo-like tumor microenvironment that provides the necessary cell-cell contact, 3D-architecture, and the influence of different cell types. The observed selective killing of cancer cells in this system suggests that the compounds are highly specific and have good potency. Mechanistically, we have determined that the compounds inhibit the Notch signaling pathway and PXR expression. Based on our preliminary studies, DCLK1 targeting by THB and THBCD resulting in suppression of both Notch signaling and PXR is a valid therapeutic strategy for colon cancers. We aim to continue developing preclinical data in the current application. In aim 1, we propose to determine the role of Notch-1 in PXR expression. In aim 2, we will perform detailed PK/PD studies of the compound and find the optimal dose to perform preclinical studies in xenotransplant and APCmin/+ mouse models. In aim 3, we propose then to continue and determine the effect of the combination of THB and THBCD with 5-fluorouracil to inhibit colon cancer growth. Effect of the compounds on Akt phosphorylation, Notch-1 activation, and DCLK1 and PXR expression in the tumor will be determined. These proposed studies would provide compelling mechanistic evidence for initiating clinical trials for the novel compounds alone and in combination. These studies will also aid in optimizing a targeted chemotherapeutic regimen and identify novel biomarkers for the future clinical studies.

描述（由申请人提供）：在美国和世界各地，结肠癌仍然是癌症相关发病率和死亡率的主要原因。许多治疗剂及其组合被用来抑制肿瘤的生长和转移。然而，这些策略的一些重大问题是药物耐药性的产生和药物副作用的增加。药物的一个关键原因耐药性是指通过各种激酶途径直接或间接靶向治疗，它们激活孕烷X受体（PXR）。因此，抑制特定途径但不诱导 PXR 的新型靶向疗法至关重要。对此，我们开发了一种新药MRLTHB和水溶性类似物MRLTHBCD，其抑制Notch-1信号传导并且不诱导PXR。当前项目的目标是进一步表征该药物，并生成作为单独或与 5-氟尿嘧啶 (5-FU) 联合用于结肠癌的口服疗法的临床前数据。在之前的研究中，我们已经确定下调双皮质素钙调蛋白样激酶 1 (DCLK1) 会抑制结肠癌异种移植物的生长，这表明靶向 DCLK1 将是治疗结肠癌的有效策略。我们现已确定 THB 和 THBCD 特异性抑制 DCLK1 激酶活性，但不影响激酶活性钙调蛋白，如激酶 CAMKII 和 CAMKIV。此外，我们还确定这些化合物可以在一种新的培养方法中抑制结肠癌细胞的生长，该方法被称为“培养皿中的肿瘤”（TiD），其中癌细胞在包括正常上皮细胞、成纤维细胞和内皮细胞的三维培养物中生长。该模型创建了一个类似体内的肿瘤微环境，提供必要的细胞间接触、3D 架构以及不同细胞类型的影响。观察到的选择性杀伤该系统中癌细胞的数量表明这些化合物具有高度特异性并且具有良好的效力。从机制上讲，我们确定这些化合物抑制 Notch 信号通路和 PXR 表达。根据我们的初步研究，THB 和 THBCD 靶向 DCLK1 导致 Notch 信号传导和 PXR 抑制，是结肠癌的有效治疗策略。我们的目标是继续开发当前应用中的临床前数据。在目标 1 中，我们建议确定 Notch-1 在 PXR 表达中的作用。在目标 2 中，我们将对化合物进行详细的 PK/PD 研究，并找到在异种移植和 APCmin/+ 小鼠模型中进行临床前研究的最佳剂量。在目标 3 中，我们建议继续确定 THB 和 THBCD 与 5-氟尿嘧啶组合抑制结肠癌生长的效果。将确定化合物对肿瘤中Akt磷酸化、Notch-1激活以及DCLK1和PXR表达的影响。这些拟议的研究将为启动新化合物单独和组合的临床试验提供令人信服的机制证据。这些研究还将有助于优化靶向化疗方案，并为未来的临床研究确定新的生物标志物。