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（由申请人提供）：肝细胞癌（HCC）是世界上最常见的实体器官肿瘤。在美国，过去二十年来，肝癌的发病率几乎翻了一番。 HCC 的预后极差，因为全身治疗大多是非特异性且无效的。最近人们的注意力集中在骨桥蛋白（OPN）作为 HCC 生长和转移的关键介质上。 OPN在肿瘤中过度表达，是晚期转移性癌症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HCC进展和转移的主要标志物。体内和体外功能获得和丧失实验均证明 OPN 在 HCC 局部生长和转移中发挥着至关重要的功能作用。 RNA适体是一类独特的治疗剂，与现有疗法相比具有多种优势，因此为分子靶向治疗提供了令人兴奋的机会。适体是短的 ss RNA 寡核苷酸，具有稳定的三维形状，可以紧密且特异性地结合选定的蛋白质靶标，从而引发生物反应。适体具有低纳摩尔至皮摩尔范围内的结合亲和力，热稳定，缺乏免疫原性，并且具有最小的批次间变异性，可有效靶向细胞外靶标。作为一种分泌性磷蛋白，OPN 是 RNA 适体介导的 HCC 生长和转移阻断的理想治疗靶点。我们分离出了针对人 OPN 的 RNA 适体 (Kd ~18 nM)。在本次拨款申请中，我们建议：1) 表征我们的 RNA 适体对 OPN 细胞表面结合、信号转导和粘附/迁移/侵袭的体外作用，2) 确定 OPN-R3 在人 HCC 鼠异种移植模型中抑制局部生长、转移和消退的体内功效，以及 3) 确定 OPN 的药效学和毒理学特征 适体优化体内剂量。我们的最终目标是将这种 OPN 适体转化为 HCC 治疗的临床领域。该资助利用RNA适体（一种新的治疗技术）来抑制原发性肝癌（世界上最常见的实体器官肿瘤）的生长和扩散。 公共卫生相关性：肝细胞癌 (HCC) 是世界上最常见的实体器官肿瘤，预后极差。目前可用的全身疗法无效。我们的研究将利用 RNA 适体（一种新的治疗技术）来预防 HCC 肿瘤的生长和扩散。