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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：
8627820
负责人：
Shrikant Anant
金额：
$ 51.17万
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/8627820
关键词：
Adverse drug effect Affect 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 Development Dose Drug Industry Drug Kinetics Drug Targeting Drug resistance Drug toxicity Endothelial Cells Epithelial Cells Fibroblasts Fluorouracil Future Gene Activation Goals Growth HCT116 Cells In Vitro Lead 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 Role Signal Transduction Stem cells System Therapeutic Therapeutic Agents Toxic effect Trans-Activators Treatment Efficacy United States Water Woman Work Xenograft procedure analog base cancer cell cancer therapy cell type chemotherapeutic agent cis acting element in vivo intravenous administration killings men mortality mouse model new therapeutic target notch protein novel novel therapeutic intervention novel therapeutics pre-clinical preclinical safety preclinical study pregnane X receptor prevent promoter public health relevance receptor expression research study therapeutic target treatment strategy tumor tumor microenvironment tumor xenograft

项目摘要

SUMMARY 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 cells. 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.

总结