Aptamer targeting of osteopontin in hepatocellular cancer

适体靶向肝细胞癌中的骨桥蛋白

• 批准号: 8298389
• 负责人: PAUL C KUO
• 金额: $ 19.51万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298389
• 关键词: Ablation; Adhesions; Affinity; Age related macular degeneration; Antisense Oligonucleotides; Applications Grants; Attention; Behavior; Behavioral; Binding; Biological; Cancer Etiology; Cell surface; Cells; Cessation of life; Clinical; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Emerging Technologies; FDA approved; Goals; Grant; Growth; Heating; Human; In Vitro; Incidence; Intervention; Knockout Mice; Lead; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Oligonucleotides; Organ; Outcome; Patients; Pharmacodynamics; Phase I Clinical Trials; Phosphoproteins; Play; Primary carcinoma of the liver cells; Proteins; RNA; Recurrence; Research; Role; Shapes; Signal Transduction; Signal Transduction Pathway; Solid; Systemic Therapy; Technology; Testing; Therapeutic Agents; Toxic effect; Translating; Tumor Promoters; United States; Xenograft Model; aptamer; cancer cell; cancer therapy; extracellular; immunogenicity; in vivo; in vivo Model; intrahepatic; loss of function; migration; novel therapeutics; osteopontin; outcome forecast; overexpression; pegaptanib; prevent; research study; response; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): Hepatocellular cancer (HCC) is the most common solid organ tumor in the world. In the US, the incidence of HCC has nearly doubled over the past two decades. HCC is associated with an extremely poor prognosis because systemic therapies are largely nonspecific and ineffective. Attention has recently focused upon osteopontin (OPN) as a key mediator of HCC growth and metastasis. OPN is overexpressed in tumors, is the major phosphoprotein secreted by malignant cells in advanced metastatic cancer, is a key mediator of tumor cell migration and metastasis, and is a lead marker of HCC progression and metastasis. Both in vivo and in vitro gain- and loss-of-function experiments demonstrate a crucial functional role for OPN in local growth and metastasis of HCC. RNA aptamers are a unique class of therapeutic agents that carries several advantages over current therapies and as such, represent an exciting opportunity for molecularly targeted therapy. Aptamers are short ss RNA oligonucleotides that assume a stable three-dimensional shape to tightly and specifically bind selected protein targets to elicit a biological response. Aptamers possess binding affinities in the low nanomolar to picomolar range, are heat stable, lack immunogenicity, and possess minimal interbatch variability to effectively target extracellular targets. As a secreted phosphoprotein, OPN is an ideal therapeutic target for RNA aptamer mediated blockade of HCC growth and metastasis. We have isolated an RNA aptamer directed against human OPN (Kd ~18 nM). In this grant application, we propose to: 1) characterize the in vitro effect of our RNA aptamer on OPN-cell surface binding, signal transduction and adhesion/migration/invasion, 2) determine the in vivo efficacy of OPN-R3 for inhibition of local growth, metastasis and regression in a murine xenograft model of human HCC, and 3) determine the pharmacodynamic and toxicologic profile of the OPN aptamer to optimize in vivo dosing. It is our ultimate goal to translate this OPN aptamer into the clinical realm for HCC therapy. This grant utilizes RNA aptamers, a new therapeutic technology, to inhibit growth and spread of primary liver cancer, the most common solid organ tumor in the world. PUBLIC HEALTH RELEVANCE: Hepatocellular cancer (HCC) is the most common solid organ tumor in the world and carries and extremely poor prognosis. Currently available systemic therapies are ineffective. Our research will utilize RNA aptamers, a new therapeutic technology, to prevent growth and spread of HCC tumors.

描述(申请人提供)：肝细胞癌是世界上最常见的实体器官肿瘤。在美国，肝癌的发病率在过去20年里几乎翻了一番。肝细胞癌预后极差，因为全身治疗在很大程度上是非特异性和无效的。骨桥蛋白(OPN)是肝细胞癌生长和转移的关键介质，近年来引起了人们的关注。OPN在肿瘤中高表达，是晚期转移癌中恶性细胞分泌的主要磷蛋白，是肿瘤细胞迁移和转移的关键介质，是肝细胞癌进展和转移的主要标志。体内和体外的功能获得和丧失实验都表明OPN在肝癌的局部生长和转移中起着重要的功能作用。RNA适配子是一类独特的治疗剂，与目前的治疗方法相比具有几个优点，因此代表着分子靶向治疗的一个令人兴奋的机会。适配子是一种短的单链RNA寡核苷酸，具有稳定的三维形状，与选定的蛋白质靶标紧密和特异地结合，从而引发生物反应。适配子具有低纳摩尔到皮摩尔范围内的结合亲和力，热稳定性，缺乏免疫原性，并具有最小的批间变异性来有效靶向细胞外靶点。作为一种分泌型磷蛋白，OPN是RNA适体介导的阻断肝癌生长和转移的理想靶点。我们分离到了一个针对人OPN(Kd~18 nm)的RNA适配子。在这项赠款申请中，我们建议：1)表征我们的RNA适配子对OPN-细胞表面结合、信号转导和黏附/迁移/侵袭的体外影响；2)确定OPN-R3在体内抑制小鼠人肝癌异种移植模型局部生长、转移和消退的有效性；3)确定OPN适配子的药效学和毒理学特征，以优化体内给药。我们的最终目标是将这种OPN适配子转化到肝癌治疗的临床领域。这笔赠款利用RNA适配子这一新的治疗技术来抑制世界上最常见的实体器官肿瘤--原发性肝癌的生长和扩散。 公共卫生相关性：肝细胞癌是世界上最常见的实体器官肿瘤，其携带和预后极差。目前可用的系统疗法是无效的。我们的研究将利用RNA适体这一新的治疗技术来防止肝癌肿瘤的生长和扩散。