Chemotherapy and anti EGFR Antibody C225 in Lung Cancer

有强有力的实验证据表明，表皮生长因子受体(EGFR)信号转导通路作为一种细胞生存机制和某些上皮性恶性肿瘤的生长维持机制发挥着重要作用。EGFR在约60%的非小细胞肺癌(NSCLC)肿瘤中过度表达。C225是一种人源化的单抗，通过与EGF竞争结合EGFR来特异性地抑制EGFR的功能，从而导致细胞生长抑制。在体内实验系统中，C225已被证明能特异性地敏化表达EGFR的肿瘤对各种细胞毒剂的影响。现在也有新的临床证据表明，C225可以使对顺铂耐药的头颈部肿瘤对顺铂敏感。在三个独立的随机试验中，新辅助化疗后手术切除已被证明能改善IIIA期非小细胞肺癌患者的存活率。然而，使用的方案的病理完全缓解率在5%到11%之间。有理由认为，新辅助方案将导致较高的病理完全应答率，将进一步改善这些患者的存活率。在这项提案中，我们将检验C225与紫杉烷和铂类药物在具有激活的EGFR信号转导途径的NSCLC肿瘤中具有协同作用的假设。临床研究的入选标准将包括表达编号1中确定的协同作用的分子决定因素的肿瘤。在临床研究的背景下，我们将把病理反应的程度与肿瘤治疗前和治疗后的EGFR激活状态联系起来。提出的研究结果将表明这种组合在治疗非小细胞肺癌方面的潜力，确定对这种组合更有可能产生反应的特定肿瘤亚群，并最终证明在随机临床试验中对这一假设的最终检验是正确的。

There is strong experimental evidence that the epidermal growth factor receptor (EGFR) signal transduction pathway plays an important role as a cell survival mechanism and to sustain the growth of certain epithelial malignancies. EGFR is overexpressed in about 60 percent of non-small cell lung cancer (NSCLC) tumors. C225 is a humanized monoclonal antibody that specifically inhibits EGFR function by competing with EGF for binding to EGFR, thus resulting in cell growth inhibition. C225 has been shown to specifically sensitize tumors expressing EGFR to the effects of a variety of cytotoxic agents in in vivo experimental systems. There is also now emerging clinical evidence that C225 can sensitize cisplatin-resistant head and neck tumors to cisplatin. Neoadjuvant chemotherapy followed by surgical resection has been shown to improve the survival of patients with stage IIIA NSCLC in three separate randomized trials. However, the pathological complete remission rate with the regimens used ranges between 5 and 11 percent. It is reasonable to assume that a neoadjuvant regimen that would result in a higher rate of pathological complete response would further improve the survival of these patients. In this proposal, we will test the hypothesis that C225 synergizes with taxanes and platinum drugs in NSCLC tumors that have an activated EGFR signal transduction pathway. For that purpose: 1) we will study the antitumor activity of taxane/platinum +/- C225 in a series of human NSCLC heterotransplants in nude mice and will identify the molecular, determinants of synergism; and 2) we will conduct a Phase II clinical study of neoadjuvant taxane/platinum + C225 in patients with stage IIIA NSCLC tumors using a 20 percent pathological complete response as primary endpoint. Entry criteria for the clinical study will include tumors expressing the molecular determinants of synergism identified under number 1. In the context of the clinical study, we will correlate the degree of pathological response with the pre- and post-therapy EGFR activation status of the tumors. The results of the studies proposed will indicate the potential of this combination in the treatment of NSCLC, identify the specific subsets of tumors that are more likely to respond to this combination, and eventually justify the definitive testing of the hypothesis in a randomized clinical trial.