Developing a novel recombinant antibody for treatment of oral cancer

开发用于治疗口腔癌的新型重组抗体

• 批准号: 8095037
• 负责人: Zhen Fan
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8095037
• 关键词: Accounting; Angiogenesis Inhibition; Angiogenesis Inhibitors; Antibodies; Binding; Blocking Antibodies; Cancer Cell Growth; Cancer Model; Cancer Patient; Cell Proliferation; Cell model; Cetuximab; Clinical; Clinical Research; DNA; Death Rate; Development; Diagnosis; Disease; Distant; Down-Regulation; Drug Delivery Systems; EGFR Protein Overexpression; Engineering; Epidermal Growth Factor Receptor; FDA approved; Fc Receptor; Genetic Engineering; Growth; Head and Neck Cancer; Hypoxia; Hypoxia Inducible Factor; Laboratories; Laboratory Study; Lead; Link; Malignant Neoplasms; Mediating; Metastatic Lesion; Monoclonal Antibodies; Mus; Neck; Neoplasm Metastasis; Nutrient; Operative Surgical Procedures; Organ; Oropharyngeal; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Play; Prevention; Primary Neoplasm; Protein Biosynthesis; Proteins; Radiation therapy; Receptor Signaling; Recombinant Antibody; Recombinant Proteins; Reporting; Role; Signal Transduction; Solid Neoplasm; Squamous cell carcinoma; Staging; Survival Rate; Technology; Testing; Time; Tumor Cell Invasion; United States; Validation; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vision; Work; Xenograft Model; Xenograft procedure; angiogenesis; bevacizumab; cancer cell; cancer diagnosis; cancer therapy; cancer type; cofactor; disorder control; hypoxia inducible factor 1; improved; interest; lymph nodes; malignant mouth neoplasm; neoplastic cell; novel; outcome forecast; overexpression; prevent; promoter; receptor; response; tumor; tumor growth

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. PUBLIC HEALTH RELEVANCE: Antiangiogenic therapy can successfully inhibit growth of primary tumors, but recent studies indicate that it may also enhance tumor invasion and metastasis potential as a result of antiangiogenic therapy-induced tumor hypoxia, which has long been recognized to promote tumor invasion and metastasis. In this study, we will test a new drug we developed that is expected not only to inhibit angiogenesis and growth of primary tumors but also to prevent antiangiogenic therapy-induced tumor hypoxic responses in oral cancer models.

描述（由申请人提供）：口腔癌约占美国诊断的所有癌症的2%。尽管治疗取得了进展，但口腔癌患者的5年生存率在几十年内没有显著提高，主要是因为口腔癌诊断时通常存在转移。抗血管生成治疗，如血管内皮生长因子（VEGF）的治疗，已被认为是一种潜在的治疗口腔癌。然而，目前批准的抗血管生成药物在其他类型癌症患者中仅延长了几个月的总生存期。此外，来自实验室和临床研究的新证据表明，虽然抗血管生成治疗抑制原发性肿瘤的生长，但由于缺氧诱导因子（HIF-1）介导的对成功的抗血管生成治疗后恶化的肿瘤缺氧的适应性逃避反应，它也可能促进肿瘤侵袭和转移。因此，似乎抗血管生成药物与抗HIF-1药物的组合将是有希望的。大约90%的口腔癌是鳞状细胞癌，一种与表皮生长因子受体（EGFR）过表达相关的亚型。西妥昔单抗是一种EGFR阻断抗体，已获得FDA批准与放疗联合治疗头颈癌，包括口腔癌。我们最近报道，西妥昔单抗可以减少低氧和常氧癌细胞中的HIF-11。在这个探索性/开发项目中，我们提出开发一种新的重组抗体，靶向VEGF和EGFR。我们的假设是，一种重组抗体，可以抑制VEGF诱导的血管生成，也降低HIF-11水平，通过抑制EGFR途径在口腔癌的作品比单剂治疗批准的抗VEGF或抗EGFR药物。我们将在口腔癌细胞模型中检验这一假设，其中VEGF和EGFR都是癌细胞生长、侵袭和转移的重要促进剂。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中对侵袭和转移的影响方面的抗肿瘤作用。我们期望所提出的工作将导致一种新型重组抗体的开发和验证，该抗体不仅抑制原发性肿瘤的生长，而且还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以通过成功预防和治疗转移性疾病来显著提高口腔癌患者的5-生存率。 公共卫生相关性：抗血管生成治疗可以成功地抑制原发性肿瘤的生长，但最近的研究表明，由于抗血管生成治疗诱导的肿瘤缺氧，它也可能增强肿瘤的侵袭和转移潜力，这一直被认为是促进肿瘤侵袭和转移的原因。在这项研究中，我们将测试我们开发的一种新药，该药物不仅有望抑制原发性肿瘤的血管生成和生长，而且还可以预防口腔癌模型中抗血管生成治疗诱导的肿瘤缺氧反应。