CELL SURFACE MARKER AND HOMING TARGET FOR ORAL SCC

这一修订方案的目标是开发一种针对高分化口腔鳞状癌的新疗法，该疗法基于一种在高分化癌细胞表面独特表达的内质网驻留蛋白的表达。高分化口腔鳞状细胞癌与其他高分化癌一样，因其有丝分裂指数低、增殖率低而难以治疗。然而，已知这些分化良好的肿瘤具有并表达内质网（ER）胶原蛋白伴侣蛋白Hsp47。虽然Hsp47特异性结合内质网中的前胶原，但在恶性肿瘤中，该蛋白逃脱内质网的保留，在细胞表面表达。我们假设这种蛋白的特殊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用于化疗或成像的靶标。这一假设将通过三个具体目标的实现来检验。这些措施包括：(1)利用随机肽库和以Hsp47为诱饵蛋白的随机显示肽的双杂交筛选，扩大Hsp47结合肽的库；(2)确定Hsp47结合肽在培养的表皮样癌细胞和实体瘤细胞表面的可用性和命运；和(3)。确定Hsp47结合肽和Hsp47单克隆抗体在口腔鳞癌异种移植中化疗药物归巢到肿瘤部位的疗效。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，他们来自马里兰大学牙科学院、医学院和格林鲍姆癌症中心。这项建议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。

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.