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

• 批准号: 8071565
• 负责人: LI MAO
• 金额: $ 30.19万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-14 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071565
• 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

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，仅在美国就估计有超过 174,470 例新肺癌病例，以及 162,460 例与肺癌相关的死亡。这些数据反映了我们在当前治疗策略下缺乏提高患者生存率和生活质量的能力。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，例如针对肺癌患者开发表皮生长因子受体（EGFR）酪氨酸激酶抑制剂和血管内皮生长因子（VEGF）抑制剂。我们最近发现，肝细胞源性生长因子（HDGF）是基质细胞和上皮细胞的有丝分裂原，在非小细胞肺癌（NSCLC）中频繁过度表达，非小细胞肺癌（NSCLC）占所有肺癌的80%以上，并且过度表达与肿瘤复发和不良生存率密切相关。我们进一步证明HDGF参与恶性转化、肿瘤进展和侵袭。我们开发了一组针对 HDGF 的中和单克隆抗体。我们的初步数据表明，这些抗体可有效抑制异种移植肿瘤模型中的肺癌生长，表明 HDGF 是一种新的治疗靶点。我们假设 HDGF 是 NSCLC 进展的关键因素和新的治疗靶点。为了检验这一假设，我们在本申请中提出了三个具体目标： 在目标 1 中，我们将通过分析原发性 NSCLC 中 HDGF 的表达并将其表达与临床病理参数相关联，确定 HDGF 作为 NSCLC 患者预后标志物的作用。 HDHF 表达与其他血管生成因子和潜在的 HDGF 下游分子之间的相关性也将被确定。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。我们将强调使用抗体作为单一药物并进行有限的组合来证明原理。在目标 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，并确定用于基于抗 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疗法的开发提供强有力的理论依据和科学知识。公众健康相关性：肝细胞生长因子 (HDGF) 是一种对肺癌进展非常重要的新型分子。本研究将评估 HDGF 作为预后标志物的作用，用于识别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单克隆抗 HDGF 抗体作为肺癌治疗药物的用途。