Developing a novel recombinant antibody for treatment of oral cancer

描述（由申请人提供）：口腔癌约占美国所有癌症诊断的2%。尽管治疗取得了进步，但几十年来口腔癌患者的5年生存率并没有显著提高，这主要是因为口腔癌确诊时通常已经出现了转移。抗血管生成治疗，如抗血管内皮生长因子（VEGF）的治疗，已被认为是口腔癌的潜在治疗方法。然而，目前批准的抗血管生成药物只能将其他类型癌症患者的总生存期延长几个月。此外，来自实验室和临床研究的新证据表明，尽管抗血管生成治疗抑制原发肿瘤的生长，但它也可能促进肿瘤的侵袭和转移，这是由于抗血管生成治疗成功后，缺氧诱导因子（HIF-1）介导的对肿瘤缺氧恶化的适应性逃避反应。因此，抗血管生成药物与抗hif -1药物联合使用似乎是有希望的。大约90%的口腔癌是鳞状细胞癌，这是一种与表皮生长因子受体（EGFR）过表达相关的亚型。西妥昔单抗（Cetuximab）是一种egfr阻断抗体，已被FDA批准与放疗联合治疗头颈癌，包括口腔癌。我们最近报道了西妥昔单抗可以降低常氧和缺氧癌细胞中的HIF-11。在这个探索性/发展性项目中，我们建议开发一种新的靶向VEGF和EGFR的重组抗体。我们的假设是，在口腔癌中，一种重组抗体可以抑制vegf诱导的血管生成，并通过抑制EGFR途径降低HIF-11水平，比使用经批准的抗vegf或抗EGFR药物的单药治疗效果更好。我们将在口腔癌细胞模型中验证这一假设，其中VEGF和EGFR都是癌细胞生长、侵袭和转移的重要促进因子。我们将比较我们的重组抗体与FDA批准的抗vegf抗体贝伐单抗和FDA批准的抗egfr抗体西妥昔单抗在转移性口腔癌异种移植物侵袭和转移方面的抗肿瘤作用。我们希望这项工作能够开发和验证一种新的重组抗体，这种抗体不仅可以抑制原发肿瘤的生长，还可以防止抗血管生成治疗诱导的侵袭和转移。这种新型重组抗体可能通过成功的预防和治疗口腔癌转移，显著提高口腔癌患者的5-生存率。

DESCRIPTION (provided by applicant): Oral cancer accounts for approximately 2% of all cancers diagnosed in the United States. Despite advances in therapy, the 5-year survival of patients with oral cancer has not significantly improved in decades, largely because metastases are usually present when oral cancer is diagnosed. Antiangiogenic therapy, such as therapy against vascular endothelial growth factor (VEGF), has been suggested as a potential treatment for oral cancer. However, currently approved antiangiogenic drugs have prolonged overall survival by only a few months in patients with other types of cancer. Furthermore, emerging evidence from laboratory and clinical studies indicates that, although antiangiogenic therapy inhibits the growth of primary tumors, it may also promote tumor invasion and metastasis owing to a hypoxia-inducible factor (HIF-1)-mediated adaptive-evasive response to worsening tumor hypoxia after successful antiangiogenic therapy. Therefore, it appears that a combination of antiangiogenic drugs with anti-HIF-1 drugs would be promising. Approximately 90% of oral cancers are squamous cell carcinoma, a subtype associated with overexpression of epidermal growth factor receptor (EGFR). Cetuximab, an EGFR-blocking antibody, is approved by the FDA in combination with radiotherapy for head and neck cancers, including oral cancers. We recently reported that cetuximab can decrease HIF-11 in both normoxic and hypoxic cancer cells. In this exploratory/developmental project, we propose to develop a novel recombinant antibody that targets both VEGF and EGFR. Our hypothesis is that a recombinant antibody that can inhibit VEGF-induced angiogenesis and also decrease the HIF-11 level through inhibition of the EGFR pathway in oral cancer works better than single-agent therapy with approved anti-VEGF or anti-EGFR drugs. We will test the hypothesis in oral cancer cell models in which both VEGF and EGFR are important promoters of cancer cell growth, invasion, and metastasis. We will compare the antitumor effects of our recombinant antibody with those of the FDA-approved anti-VEGF antibody bevacizumab and the FDA- approved anti-EGFR antibody cetuximab in terms of the impact on invasion and metastasis in metastatic oral cancer xenografts. We expect the proposed work to lead to development and validation of a novel recombinant antibody that not only inhibits growth of primary tumors but also prevents antiangiogenic therapy-induced invasion and metastasis. Such a novel recombinant antibody may significantly improve the 5-survival rate for patients with oral cancer through successful prevention and treatment of metastatic disease.