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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侵袭性癌症，具有高度转移性播散的倾向。尽管黑色素瘤治疗最近取得了进展，但大多数患有转移性疾病的患者并没有经历过从当前的治疗方案中获得持久的益处。事实上，现有的靶向和癌症免疫治疗治疗方法不能直接抑制肿瘤转移，而肿瘤转移是大多数癌症相关死亡的原因。因此，开发专门针对黑色素瘤细胞固有的促转移途径的新药物可以大大改善治疗效果并减少脱靶毒性。观察到的贩运过程在传播转移性癌症方面，至少部分类似于白细胞归巢范式，即连续的多步粘附级联涉及细胞束缚和在微血管内皮上滚动，然后整合素介导的阻滞和跨内皮迁移至次级组织。白细胞归巢具有依赖性内皮细胞上专门的整合素异二聚体及其同源配体。然而，迄今为止，这些独特的白细胞归巢整合素亚群的表达尚未在黑色素瘤中得到描述。我们的初步研究首次证明，传统上，整合素异二聚体的异常表达据认为仅限于白细胞，具有高转移能力的黑色素瘤细胞亚群。病人中原发性黑色素瘤、癌细胞内在整合素阳性与前哨淋巴结转移相关。这些整合素异二聚体的黑色素瘤特异性抑制抑制了内皮粘附，并且显着阻断人类黑色素瘤临床前小鼠模型的生长和转移形成。这些范式—— 不断变化的发现将白细胞归巢整合素确定为肿瘤细胞传播的新介质。虽然造血整合素靶向方法，包括人源化抗体，已经被为治疗患有炎症和自身免疫性白细胞运输障碍的患者而开发，它们从未在癌症背景下进行过检查。在本提案中，我们新研究了治疗方法这些经过验证且易于使用的整合素抑制剂在阻止转移扩散方面的效用临床前黑色素瘤模型。我们的具体目标是 1) 剖析黑色素瘤细胞固有的机制归巢整合素诱导和功能激活，并定义整合素糖基化状态和异二聚体不同进展阶段患者肿瘤生物样本的成分，以及 2) 检查治疗效果 CRISPR/Cas-9介导的白细胞整合素敲除或临床级整合素抑制剂的功效最初配制用于治疗临床前黑色素瘤模型中的免疫运输疾病。我们有组建了黑色素瘤转移、白细胞归巢、基因编辑、皮肤病理学专家团队，和糖生物学领域，以实现该提案的翻译相关目标。我们的结果研究可以确定黑色素瘤细胞表达的白细胞整合素及其糖结构决定因素：选择性抑制转移扩散的新治疗靶点。