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Functional analysis of a novelintegrin-dependent metastasis pathway in melanoma

黑色素瘤中新型整合素依赖性转移途径的功能分析

基本信息

批准号：
10308517
负责人：
Steven Russell Barthel
金额：
$ 50.84万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10308517
关键词：
Adhesions Adhesives Antibodies Autoimmune Autoimmunity Biological Assay Blocking Antibodies Blood Cells CD44 gene CRISPR/Cas technology Cell Adhesion Cell Lineage Cells Cessation of life Clinical Data Dermatopathology Development Disease Disseminated Malignant Neoplasm Endothelial Cells Endothelium Epitopes FDA approved Frequencies Fruit Genes Glycobiology Glycoproteins Growth Hematopoietic Home Homing Human ITGAM gene ITGAX gene ITGB2 gene Immune Inflammation Inflammatory Integrin Inhibition Integrins Intercellular Adhesion Molecules Intercellular adhesion molecule 1 Knock-out Knockout Mice Lectin Leukocyte Trafficking Leukocytes Ligands Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator of activation protein Melanoma Cell Metastatic Melanoma Metastatic Neoplasm to Lymph Nodes Migration Assay Modality Modeling Molecular Conformation Mus Neoplasm Metastasis New Agents Non-Malignant Outcome Pathway interactions Patient imaging Patient-Focused Outcomes Patients Peripheral Pharmacology Polysaccharides Positive Lymph Node Predisposition Primary Neoplasm Process Prognosis RNA Interference Reagent Regulation Research Project Grants Role Sentinel Lymph Node Solid Neoplasm System T-Lymphocyte Testing Therapeutic Time Tissues Toxic effect Treatment Efficacy Treatment outcome Tumor Cell Line Tumor-Derived Variant Vertebral column antagonist base cancer cell cancer immunotherapeutics cellular targeting cohort crosslink glycosylation hemodynamics human model humanized antibody immune-related adverse events improved in vivo in vivo imaging inhibitor innovation insight leukocyte homing luminescence macrophage melanoma migration mouse model neoplastic cell new therapeutic target novel novel therapeutics pre-clinical therapeutic target tool trafficking translational study tumor tumor progression tumor xenograft tumorigenesis

项目摘要

Human malignant melanoma is an aggressive cancer with high propensity for metastatic dissemination. Despite recent advances in melanoma therapy, most patients with metastatic disease do not experience durable benefit from current treatment options. Indeed, existing targeted and cancer immunotherapeutic modalities do not directly inhibit tumor metastasis, which accounts for most cancer-related deaths. Accordingly, the development of new agents that specifically target pro-metastatic pathways intrinsic to melanoma cells could greatly improve treatment outcomes and reduce off-target toxicities. The trafficking processes observed in disseminating metastatic cancers resemble, at least in part, the leukocyte homing paradigm, a sequential multistep adhesive cascade involving cell tethering and rolling on microvascular endothelium, followed by integrin-mediated arrest and transendothelial migration into secondary tissues. Leukocyte homing is dependent on specialized integrin heterodimers and their cognate ligands on endothelial cells. To date, however, expression of these distinct leukocytic homing integrin subsets has not been described in melanoma. Our preliminary studies demonstrate, for the first time, aberrant expression of integrin heterodimers, conventionally thought to be restricted to leukocytes, by melanoma cell subsets with high metastatic capacity. In patient primary melanomas, cancer cell-intrinsic integrin positivity correlated with sentinel lymph node metastases. Melanoma-specific inhibition of these integrin heterodimers suppressed endothelial adhesion and significantly blocked growth and metastasis formation in preclinical mouse models of human melanoma. These paradigm- shifting findings identify leukocytic homing integrins as novel mediators of tumor cell dissemination. While hematopoietic integrin targeting approaches, including humanized antibodies, have already been developed for the treatment of patients with inflammatory and autoimmune leukocyte trafficking disorders, they have never been examined in the context of cancer. In this proposal, we newly investigate the therapeutic utility of these validated and readily available integrin inhibitors in blocking metastatic dissemination in preclinical melanoma models. Our specific aims are to 1) dissect mechanisms of melanoma cell-intrinsic homing integrin induction and functional activation, and define integrin glycosylation states and heterodimer composition in patient tumor biospecimens at various stages of progression, and 2) examine the therapeutic efficacy of CRISPR/Cas-9-mediated leukocytic integrin knockout or clinical-grade integrin inhibitors originally formulated for the treatment of immune trafficking disorders, in preclinical melanoma models. We have assembled a team of experts in the melanoma metastasis, leukocyte homing, gene editing, dermatopathology, and glycobiology fields, to bring to fruition the translationally relevant aims of this proposal. Results from our studies could establish melanoma cell-expressed leukocytic integrins and their glycostructural determinants as novel therapeutic targets for selective inhibition of metastatic dissemination.

人类恶性黑色素瘤是一种具有高转移性传播倾向的侵袭性癌症。