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HDGF: a novel biomarker and therapetic target of lung cancer

HDGF：肺癌的新型生物标志物和治疗靶点

基本信息

批准号：
8250458
负责人：
LI MAO
金额：
$ 39.06万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-14 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250458
关键词：
Accounting Adenocarcinoma Aftercare Angiogenesis Inhibitors Angiogenic Factor Animals Antibodies Behavior Biological Biological Markers Blood Vessels Cancer Center Cancer Etiology Cancer Patient Cancer cell line Cell Communication Cell Line Cessation of life Chest Clinical Clinical Research Conditioned Culture Media Cytotoxic agent Data Databases Development Disease Disease-Free Survival Dose Enrollment Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Epithelial Cells Excision Fibroblasts Growth Head and neck structure Health Hepatocyte Growth Factor Immunocompetent In Vitro Knowledge Large Cell Carcinoma Malignant - descriptor Malignant neoplasm of lung Medical Oncology Mesenchymal Mitogens Modeling Molecular Molecular Abnormality Molecular Profiling Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Outcome Patient Selection Patients Primary Neoplasm Prognostic Marker Quality of life Regimen Relapse Resectable Resistance Risk Factors Role Smooth Muscle Myocytes Squamous cell carcinoma Staging Stromal Cells Testing Therapeutic Therapeutic Agents Therapeutic Effect Tumor Burden Tumorigenicity United States Vascular Endothelial Growth Factors Woman Xenograft Model angiogenesis base cancer therapy cell stroma epithelial to mesenchymal transition follow-up hepatoma cell hepatoma-derived growth factor improved in vivo Model inhibitor/antagonist men mortality mouse model neutralizing antibody neutralizing monoclonal antibodies new therapeutic target novel overexpression prospective research study response success therapeutic target treatment strategy tumor tumor growth tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related death in the United States in both men and women. In 2006, more than 174,470 new cases of lung cancer are estimated in the United States alone, and 162,460 of lung cancer-related death. The data reflect our lack of ability to improve survival and quality of life of the patients under current treatment strategies. Targeted therapy, a newly emerged therapeutic approach aiming key molecular abnormalities in cancer progression, has shown encouraging results, such as the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and vascular endothelial growth factor (VEGF) inhibitors for patients with lung cancer. We recently discovered that hepatoma-derived growth factor (HDGF), a mitogen for both stroma cells and epithelial cells, is frequently overexpression in non-small cell lung cancer (NSCLC), which accounts for >80% of all lung cancers, and the overexpression is strongly correlated with tumor relapse and poor survivals. We further demonstrated that HDGF is involved in malignant transformation, tumor progression, and invasion. We have developed a panel of neutralizing monoclonal antibodies against HDGF. Our preliminary data show that the antibodies are effective in inhibiting lung cancer growth in xenograft tumor models, suggesting HDGF is a novel therapeutic target. We hypothesize that HDGF is a critical factor in progression of NSCLC and a novel therapeutic target. To test the hypothesis, we proposed three specific aims in this application: In Aim 1, we will determine the role of HDGF as a prognostic marker for patients with NSCLC by analyzing expression of HDGF in primary NSCLC and correlating the expression with clinicopathologic parameters. The correlation between HDHF expression and other angiogenic factors and potential HDGF downstream molecules will also be determined. In Aim 2, we will determine the therapeutic role of HDGF neutralizing monoclonal antibodies in NSCLC xenograft models and to reveal potential mechanisms of the anti-tumor effects. We will emphasize the use of the antibodies as a single agent with limited combination to prove of principles. In Aim 3, we will verify the therapeutic effects of the HDGF neutralizing antibody based regimens in heterotransplant tumor models and to identify selective and/or predictive biomarkers for anti-HDGF based therapy. The success of the project will provide strong rationale and scientific knowledge to guide development of anti-HDGF therapy for patients with lung cancer. PUBLIC HEALTH RELEVANCE: Hepatoma-derived growth factor (HDGF) is a novel molecule important for lung cancer progression. This study will evaluate the role of HDGF as a prognostic marker for identifying lung cancer patients likely to recur or metastasize after curative surgical treatment. We will also evaluate our newly developed neutralizing monoclonal anti-HDGF antibodies for their utility as therapeutic agents in lung cancer treatment.

描述（由申请人提供）：肺癌是美国男性和女性癌症相关死亡的主要原因。2006年，仅在美国估计就有超过174，470例肺癌新发病例，162，460例肺癌相关死亡。这些数据反映了我们在目前的治疗策略下缺乏改善患者生存和生活质量的能力。靶向治疗是一种针对癌症进展中关键分子异常的新出现的治疗方法，已显示出令人鼓舞的结果，例如用于肺癌患者的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂和血管内皮生长因子（VEGF）抑制剂的开发。我们最近发现，肝癌衍生生长因子（hepatoma-derived growth factor，HDGF）是基质细胞和上皮细胞的促分裂剂，在占所有肺癌的80%以上的非小细胞肺癌（non-small cell lung cancer，NSCLC）中频繁过表达，并且过表达与肿瘤复发和低生存率密切相关。我们进一步证实HDGF参与恶性转化、肿瘤进展和侵袭。我们已经开发了一组针对HDGF的中和性单克隆抗体。我们的初步数据显示，抗体在异种移植肿瘤模型中有效抑制肺癌生长，表明HDGF是一种新的治疗靶点。我们推测HDGF是NSCLC进展的关键因素，也是一个新的治疗靶点。为了验证这一假设，我们提出了三个具体的目标，在本申请中：在目标1中，我们将确定HDGF作为NSCLC患者的预后标志物的作用，通过分析HDGF在原发性NSCLC中的表达，并将表达与临床病理参数相关联。还将确定HDHF表达与其他血管生成因子和潜在HDGF下游分子之间的相关性。在目标2中，我们将确定HDGF中和单克隆抗体在NSCLC异种移植模型中的治疗作用，并揭示抗肿瘤作用的潜在机制。我们将强调使用的抗体作为一个单一的代理有限的组合，以证明的原则。在目的3中，我们将验证基于HDGF中和抗体的方案在异种移植肿瘤模型中的治疗效果，并鉴定用于基于抗HDGF的治疗的选择性和/或预测性生物标志物。该项目的成功将为指导肺癌患者抗HDGF治疗的发展提供强有力的理论基础和科学知识。公共卫生相关性：肝癌衍生生长因子（HDGF）是一种对肺癌进展很重要的新型分子。本研究将评估HDGF作为肺癌患者预后标志物的作用，以确定肺癌患者在根治性手术治疗后可能复发或转移。我们还将评估我们新开发的中和性单克隆抗HDGF抗体作为肺癌治疗剂的效用。