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Targeting CCL20-CCR6 Interactions in Colorectal Cancer

靶向结直肠癌中的 CCL20-CCR6 相互作用

基本信息

批准号：
10265342
负责人：
Jason Samuel Gold
金额：
--
依托单位：
VA BOSTON HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265342
关键词：
Adoption Affect CCL20 gene CCR6 gene Cancer Etiology Cell Proliferation Cells Cessation of life Clinical Trials Colon Carcinoma Colorectal Cancer Colorectal Neoplasms Country Data Development Diagnosis Dichloromethylene Diphosphonate Disease Elements Epithelial Cells Feedback Growth Health Human Immune Immune system Immunotherapy Impairment In Vitro Incidence Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intestines Investigation Isogenic transplantation Ligands Light Link Malignant Neoplasms Mediating Mediator of activation protein Modeling Mus Neoplasm Metastasis Neoplasm Transplantation Neoplastic Epithelial Cell Oral Outcome Pathway interactions Patients Play Prevention Production Role Signal Transduction Signaling Molecule Stromal Cells Stromal Neoplasm Testing Therapeutic Transplantation Tumor Promotion Veterans adenoma arm base cancer cell cancer therapy carcinogenesis chemokine chemokine receptor clinical practice clinically relevant colon cancer cell line colorectal cancer progression colorectal cancer treatment effective therapy experimental study human model in vivo inhibitor/antagonist macrophage migration monocyte mouse model neoplastic neoplastic cell novel overexpression patient subsets receptor small molecule small molecule inhibitor therapeutic target therapeutically effective treatment strategy tumor tumor growth

项目摘要

Nearly 1 in 20 people in the U.S. will be diagnosed with colorectal cancer in their lifetime, and over 1/3 of these will die from the disease. In fact, colorectal cancer is the second leading cause of cancer-related deaths in this country. Advances in prevention and treatment have made only a modest impact on incidence and survival. Novel treatment strategies for colorectal cancer are clearly needed. Chemokines have emerged as a crucial link between tumor-promoting inflammation and cancer. CCR6 is the only known receptor for the inflammatory chemokine CCL20, which in turn is the only known ligand for CCR6. Several lines of evidence suggest that interactions between the inflammatory chemokine CCL20 and its receptor CCR6 play a key role in the development and progression of colorectal cancer. Correlative evidence has suggested a possible role of CCR6 and CCL20 in promoting colorectal tumor growth, invasion and metastasis. To date, however, beyond our preliminary results, there is a paucity of in vivo data on the effect of disrupting CCL20-CCR6 interactions in colorectal cancer in the setting of an intact immune system. We have demonstrated that both CCL20 and CCR6 are upregulated in human colon cancers. We have found that deficiency of CCR6 is associated with a dramatic decrease in adenoma formation in a model of spontaneous intestinal carcinogenesis and a marked decrease in tumor growth in a syngeneic transplantable tumor model. We have observed that CCL20 signaling through CCR6 induces further secretion of CCL20, and this in turn promotes proliferation and migration in colorectal cancer cells. In addition to the epithelial cell effects of CCL20-CCR6 interactions, a stromal effect is evidenced by the fact that in the tumor challenge experiments, the transplanted colon cancer cells expressed CCR6 in both arms, yet growth was delayed in CCR6-deficient host mice. We have found that CCR6 deficiency is associated with decreased macrophage migration into adenomas and transplanted colon cancers. We have further demonstrated that CCL20-CCR6 interactions indeed induce monocyte/macrophage migration in vitro and in vivo. Furthermore, we have observed that growth of transplanted colon cancer tumors is delayed by depletion of tumor macrophages. Lastly, we have found that tumor macrophages secrete inflammatory mediators, which in turn induce proliferation of colon cancer cells. In aggregate our preliminary results imply that CCL20-CCR6 signaling promotes colorectal cancer through a direct effect on neoplastic cancer cells as well as through effects on tumor stromal cells such as macrophages. We have recently begun to test a novel, orally-available small molecule CCR6 inhibitor. Our preliminary data show that this molecule can inhibit the CCL20 auto feedback loop, colorectal cancer cell proliferation, and monocyte migration in vitro. Thus we hypothesize that targeting interactions between CCL20 and CCR6 is effective for the treatment of colorectal cancer. To test this hypothesis and to further elucidate the role of CCR6 and CCL20 in colorectal cancer, we aim to: 1) establish the impact of targeting CCL20-CCR6 interactions on the neoplastic epithelial cells in colorectal cancer; 2) establish the outcome of targeting CCL20-CCR6 interactions on tumor-promoting stroma in colorectal cancer; and 3) establish the efficacy of targeting CCL20-CCR6 interactions in translationally relevant models of human colorectal cancer. The proposed studies will shed light on the role of the chemokine receptor CCR6 and its ligand CCL20 in colorectal cancer. We believe that these studies will determine the clinical relevance and therapeutic importance of interactions between CCR6 and CCL20 in this disease and should pave the way to successful targeting of this pathway in human patients.

在美国，将近1/ 20的人会在一生中被诊断出患有结肠直肠癌，超过1/3的人