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略性癌症，具有高倾向转移性传播。尽管黑色素瘤疗法最近进展，但大多数转移性疾病的患者却没有经历当前的治疗选择持续益处。确实，现有的靶向和癌症免疫治疗性模式不会直接抑制肿瘤转移，这占大多数与癌症相关的死亡。因此，专门靶向黑色素瘤细胞固有的促靶途径的新药物的发展可以大大改善治疗结果并降低脱靶毒性。贩运过程观察到在传播转移性癌症时，至少部分类似于白细胞寄养范式多步粘性级联反应，涉及细胞链接和在微血管内皮上滚动，然后是整联蛋白介导的停滞和跨内皮迁移到二次组织中。白细胞归依赖在内皮细胞上的专用整联蛋白异二聚体及其同源配体上。但是，迄今为止在黑色素瘤中尚未描述这些独特的白细胞归巢整合素亚蛋白子集的表达。我们的初步研究表明，首次表明整联蛋白异二聚体异常表达，通常被认为是由具有高转移能力的黑色素瘤细胞亚群限制在白细胞的。在病人中原发性黑色素瘤，癌细胞内整合素阳性与哨兵淋巴结转移相关。这些整联蛋白异二聚体的黑色素瘤特异性抑制抑制了内皮粘附，并显着明显在人黑色素瘤的临床前小鼠模型中阻碍了生长和转移形成。这些范式 - 转变的发现将白细胞归巢整合素视为肿瘤细胞传播的新型介体。虽然造血整合蛋白靶向方法（包括人源化抗体）已经是开发用于治疗炎症和自身免疫性白细胞运输障碍的患者在癌症的背景下从未检查过。在此提案中，我们新研究这些经过验证且随时可用的整联蛋白抑制剂的实用性在阻止转移性传播中临床前黑色素瘤模型。我们的具体目的是1）剖析黑色素瘤细胞中性机制将整合素诱导和功能激活归为归因，并定义整联蛋白糖基化态和异二聚体在各个进展阶段，患者肿瘤生物测量的组成，2）检查治疗性 CRISPR/CAS-9介导的白细胞整合蛋白敲除或临床级整联蛋白抑制剂的功效最初是临床前黑色素瘤模型中用于治疗免疫贩运障碍的制定。我们有组建了一个黑色素瘤转移，白细胞归巢，基因编辑，皮肤病理学的专家团队和糖生物学领域，以实现该提案的翻译相关目的。我们的结果研究可以建立黑色素瘤细胞表达的白细胞整合素及其糖结构决定因素为选择性抑制转移性传播的新型治疗靶标。