HDGF: a novel biomarker and therapetic target of lung cancer

描述(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例新的肺癌病例，以及162,460例与肺癌相关的死亡。这些数据反映了在目前的治疗策略下，我们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，例如开发出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。我们最近发现，肝癌衍生生长因子(HDGF)在非小细胞肺癌(NSCLC)中经常过度表达，它是基质细胞和上皮细胞的有丝分裂原，占所有肺癌的80%，并且过度表达与肿瘤复发和不良生存密切相关。我们进一步证明了HDGF参与了恶性转化、肿瘤进展和侵袭。我们研制了一组中和抗HDGF的单抗。我们的初步数据显示，这些抗体在异种移植瘤模型中对抑制肺癌生长有效，表明HDGF是一个新的治疗靶点。我们假设HDGF是NSCLC进展中的一个关键因素和一个新的治疗靶点。为了验证这一假设，我们提出了三个具体的应用目标：在目标1中，我们将通过分析HDGF在NSCLC中的表达并将其表达与临床病理参数相关联，来确定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。在目的2中，我们将确定HDGF中和单抗在NSCLC异种移植模型中的治疗作用，并揭示其潜在的抗肿瘤作用机制。我们将强调使用抗体作为单一试剂与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，并为基于抗HDGF的治疗寻找选择性和/或预测性的生物标志物。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依据和科学知识。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分子。本研究将评估HDGF作为判断肺癌患者在根治性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抗HDGF单抗在肺癌治疗中的应用。

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.