HDGF: a novel biomarker and therapetic target of lung cancer

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，估计仅在美国就有超过174,470例肺癌新病例，162,460例肺癌相关死亡。这些数据反映了我们在现有治疗策略下改善患者生存和生活质量的能力不足。靶向治疗是一种新兴的治疗方法，针对癌症进展中的关键分子异常，已经显示出令人鼓舞的结果，例如表皮生长因子受体（EGFR）酪氨酸激酶抑制剂和血管内皮生长因子（VEGF）抑制剂在肺癌患者中的应用。我们最近发现肝癌源性生长因子（HDGF）是间质细胞和上皮细胞的有丝分裂原，在非小细胞肺癌（NSCLC）中经常过表达，而非小细胞肺癌占所有肺癌的80%左右，并且过表达与肿瘤复发和低生存率密切相关。我们进一步证明HDGF参与恶性转化、肿瘤进展和侵袭。我们已经开发了一组抗HDGF的中和单克隆抗体。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，提示HDGF是一个新的治疗靶点。我们假设HDGF是NSCLC进展的关键因素，也是一种新的治疗靶点。为了验证这一假设，我们提出了本应用的三个具体目标：在Aim 1中，我们将通过分析HDGF在原发性非小细胞肺癌中的表达并将其与临床病理参数相关联，确定HDGF作为非小细胞肺癌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HDGF下游分子的相关性也将被确定。在Aim 2中，我们将确定HDGF中和单克隆抗体在非小细胞肺癌异种移植模型中的治疗作用，并揭示其抗肿瘤作用的潜在机制。我们将强调使用抗体作为一个单一的药物，有限的组合，以证明原则。在Aim 3中，我们将验证基于HDGF中和抗体的方案在异源移植肿瘤模型中的治疗效果，并确定基于抗HDGF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：肝癌源性生长因子（HDGF）是一种对肺癌进展很重要的新分子。本研究将评估HDGF作为肺癌患者手术治疗后复发或转移的预后标志物的作用。我们还将评估我们新开发的中和性单克隆抗hdgf抗体在肺癌治疗中的效用。

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.