Targeting of alpha v beta 6 integrin in oral cancer

α v beta 6 整合素在口腔癌中的靶向作用

• 批准号: 6783658
• 负责人: JULIE L SUTCLIFFE
• 金额: $ 16.31万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-10 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6783658
• 关键词: diagnosis design /evaluation; drug screening /evaluation; enzyme linked immunosorbent assay; immunocytochemistry; integrins; laboratory mouse; neoplasm /cancer diagnosis; oral facial restoration material; peptides; positron emission tomography; protein binding; protein protein interaction; radiotracer; squamous cell carcinoma

DESCRIPTION (provided by applicant): The goal is to develop novel ava6-targeting peptides that selectively locate to ava6 positive tumors in vivo. Oral squamous cell carcinoma (SCC) accounts for 5.5% of all human malignancies worldwide. Primary treatment is radical often mutilating surgery. Since mortality from oral SCC has remained at greater than 50% for decades, novel strategies to limit its recurrence and invasive-potential are desperately needed. We believe that the cell surface expressed integrin ava6 offers and excellent target for both imaging (early detection) and therapy of oral cancer. Novel ava6-targeting peptides will be identified using the "One-Bead-One-Compound" random and rational combinatorial cyclic-peptide libraries. 4-[19F]-fluorobenzoyl will be incorporated into the peptide library as an approach to transition the identified sequences into a radiolabeled peptide for imaging using MicroPET II and fluorine-18 chemistry. The peptide libraries will be screened against immobilized integrins as well as cell lines to establish their selectivity and specificity. Peptide radiolabeling will be performed using a solid-phase approach. The peptidyl resin will be radiolabeled using 4-[18F]fluorobenzoic acid. This method is highly flexible, is rapid and amenable to automation. Once successful candidates have been identified as highly selective towards ava6 high resolution screening in mice in vivo using MicroPET II will be performed. By the end of year 2 it is anticipated that several potential ava6-targetingpeptides will be identified. The second part of this proposal we will investigate the ava6-targetingpeptides in vivo in mice using the small animal scanner MicroPET II. Standard immunohistochemistry and phosphor imaging technologies will be used to correlate radiotracer distribution in tumors with integrin expression. In vitro and structural activity experiments will be performed to explain sequence specificity and affinity.

描述（由申请人提供）： 目标是开发新型 ava6 靶向肽，在体内选择性定位 ava6 阳性肿瘤。口腔鳞状细胞癌 (SCC) 占全球所有人类恶性肿瘤的 5.5%。主要治疗是根治性手术，通常是残肢手术。由于口腔鳞状细胞癌的死亡率几十年来一直保持在 50% 以上，因此迫切需要限制其复发和侵袭潜力的新策略。我们相信细胞表面表达的整合素 ava6 为口腔癌的成像（早期检测）和治疗提供了极好的靶标。 将使用“一珠一化合物”随机和合理组合环肽库来鉴定新型 ava6 靶向肽。 4-[19F]-氟苯甲酰基将被纳入肽库中，作为将已识别序列转换为放射性标记肽的方法，以便使用 MicroPET II 和氟 18 化学进行成像。将针对固定化整合素以及细胞系筛选肽库，以确定其选择性和特异性。肽放射性标记将使用固相方法进行。将使用 4-[18F]氟苯甲酸对肽基树脂进行放射性标记。这种方法高度灵活、快速且适合自动化。一旦成功的候选者被确定为对 ava6 具有高度选择性，将使用 MicroPET II 在小鼠体内进行高分辨率筛选。到第二年年底，预计将鉴定出几种潜在的 ava6 靶向肽。该提案的第二部分，我们将使用小型动物扫描仪 MicroPET II 在小鼠体内研究 ava6 靶向肽。标准免疫组织化学和荧光成像技术将用于将肿瘤中放射性示踪剂的分布与整合素表达相关联。将进行体外和结构活性实验来解释序列特异性和亲和力。