CELL SURFACE MARKER AND HOMING TARGET FOR ORAL SCC

口腔鳞状细胞癌的细胞表面标记和归巢目标

• 批准号: 6379912
• 负责人: JOHN J SAUK
• 金额: $ 25.25万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6379912
• 关键词: antineoplastics; athymic mouse; binding proteins; biomarker; cell membrane; doxorubicin; heat shock proteins; monoclonal antibody; neoplasm /cancer chemotherapy; neoplastic growth; nonhuman therapy evaluation; oral pharyngeal neoplasm; peptide library; pharmacokinetics; protein protein interaction; squamous cell carcinoma; tissue /cell culture; yeast two hybrid system

This revised proposal has as an objective the development of a novel therapy for well-differentiated oral squamous carcinoma based on targeting the expression of an endoplasmic reticulum resident protein that is uniquely expressed on the cell surface of well-differentiated carcinomas. Well-differentiated oral squamous cell carcinomas like other well-differentiated carcinomas are difficult to treat because of their low mitotic indices and proliferation rates. However, these well- differentiated neoplasms are known to possess and express an endoplasmic reticulum (ER) collagen chaperone, Hsp47. Although Hsp47 specifically binds procollagen in the ER, in malignancy the protein escapes ER retention to be expressed on the cell surface. We hypothesize that the specific peptide binding characteristics of this protein and unique location in malignancy provides a marker that may serve as a target to which drugs or contrast agents may be directed for chemotherapy or imaging. This hypothesis will be tested through the accomplishment of three specific aims. These include: (1) Expand the repertoire of Hsp47-binding peptides by utilizing random peptide libraries and two-hybrid screening of random displayed peptides with Hsp47 as a bait protein; (2) Determine the availability and fate of Hsp47 binding peptides on the cell surface of epidermoid carcinoma cells in culture and in solid tumors; and (3). Determine the efficacy of Hsp47-binding peptides and Hsp47 monoclonal antibodies in homing chemotherapeutic drugs to tumor sites in oral squamous carcinoma xenografts. To accomplish these aims we have assembled a collaborative team of pathologists, molecular biologists, oncologists, and experts in developmental therapeutics that encompass the University of Maryland's Schools of Dentistry, Medicine and The Greenbaum Cancer Center. The ultimate success of this proposal will be determined by the impact that such an approach has on reducing the morbidity and mortality of oral cancer.

该修订提案的目标是开发一种针对高分化口腔鳞状细胞癌的新疗法，该疗法基于靶向内质网驻留蛋白的表达，该蛋白在高分化癌的细胞表面上独特表达。 高分化口腔鳞状细胞癌与其他高分化癌一样，由于其有丝分裂指数和增殖率低而难以治疗。 然而，已知这些分化良好的肿瘤拥有并表达内质网 (ER) 胶原伴侣 Hsp47。 尽管 Hsp47 特异性结合 ER 中的原胶原，但在恶性肿瘤中，该蛋白会逃脱 ER 滞留，在细胞表面表达。我们假设这种蛋白质的特异性肽结合特性和在恶性肿瘤中的独特位置提供了一种标记物，可以作为药物或造影剂可用于化疗或成像的靶点。 这一假设将通过三个具体目标的实现来检验。 其中包括：（1）利用随机肽库和以Hsp47为诱饵蛋白的随机展示肽的二杂交筛选来扩展Hsp47结合肽的库； (2) 确定培养物和实体瘤中表皮样癌细胞细胞表面上 Hsp47 结合肽的可用性和命运；和（3）。确定 Hsp47 结合肽和 Hsp47 单克隆抗体将化疗药物归巢到口腔鳞状细胞癌异种移植物肿瘤部位的功效。 为了实现这些目标，我们组建了一个由病理学家、分子生物学家、肿瘤学家和发育治疗学专家组成的合作团队，其中包括马里兰大学牙科学院、医学院和格林鲍姆癌症中心。 该提案的最终成功将取决于这种方法对降低口腔癌发病率和死亡率的影响。