PERTURBATION OF HYALURONAN FUNCTION IN CANCER

癌症中透明质酸功能的扰动

• 批准号: 6377441
• 负责人: BRYAN P TOOLE
• 金额: $ 27.37万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377441
• 关键词: Adenoviridae; CD44 molecule; binding proteins; breast neoplasms; cellular oncology; growth inhibitors; human tissue; hyaluronate; intermolecular interaction; laboratory mouse; laboratory rat; metastasis; neoplasm /cancer therapy; neoplastic growth; neoplastic process; ovary neoplasms; protein structure function; tissue /cell culture; transfection /expression vector; western blottings

DESCRIPTION (adapted from applicant's abstract): Hyaluronan and its cell surface receptors, CD44 and RHAMM, are involved in the cascade of events that lead to growth and metastasis of several tumor types. Transfection of tumor cells with soluble, hyaluronan-binding forms of CD44 or treatment with hyaluronan oligomers inhibits murine mammary carcinoma or melanoma growth in vivo, as well as formation of metastatic nodules in the lung after dissemination from the vasculature. Thus hyaluronan interactions are an essential contributor to progression of at least some tumor types and introduction of reagents that perturb hyaluronan interactions is likely to be therapeutically effective. Thus the major objective of this proposal is to design recombinant adenoviruses driving efficient production of hyaluronan-binding polypeptides that effectively inhibit tumor progression, but are engineered to have minimal side effects by removing non-hyaluronan-binding domains to whatever extent is possible without losing efficacy. The relative efficacy of recombinant adenoviral constructs encoding hyaluronan-binding polypeptides composed only of hyaluronan-binding domains (i.e., link modules), or of hyaluronan-binding motifs within a neutral background, will be compared to constructs encoding soluble CD44's that contain more extensive extracellular domains, in the murine mammary carcinoma system used previously. Successful constructs will then be tested in vivo for their ability to inhibit rat gliomal invasion and to allay human breast and ovarian carcinomas, grown in nude mice, at different stages of progression. Such constructs could be used widely for experimental manipulations in numerous systems and may ultimately lead to useful strategies for gene therapy in cancer patients.

描述（改编自申请人的摘要）：透明质酸及其细胞 表面受体 CD44 和 RHAMM 参与级联事件 导致多种肿瘤类型的生长和转移。肿瘤转染 具有可溶性、透明质酸结合形式的 CD44 的细胞或用 透明质酸寡聚物抑制小鼠乳腺癌或黑色素瘤的生长 体内，以及肺部转移结节的形成 从脉管系统传播。因此透明质酸相互作用是 至少某些肿瘤类型的进展的重要贡献者 引入干扰透明质酸相互作用的试剂可能是 治疗有效。因此，该提案的主要目标是 设计重组腺病毒以促进高效生产 透明质酸结合多肽可有效抑制肿瘤进展，但 通过去除非乙酰透明质酸结合而被设计成具有最小的副作用 域可以在不失去效力的情况下达到任何可能的程度。亲戚 编码乙酰透明质酸结合的重组腺病毒构建体的功效 仅由乙酰透明质酸结合结构域（即连接模块）组成的多肽， 或中性背景内的透明质酸结合基序，将进行比较 构建编码可溶性 CD44 的包含更广泛的细胞外 域，在先前使用的小鼠乳腺癌系统中。成功的 然后将在体内测试构建体抑制大鼠神经胶质细胞瘤的能力 侵袭并减轻在裸鼠中生长的人类乳腺癌和卵巢癌， 在不同的发展阶段。此类结构可广泛用于 在许多系统中进行实验操作，并可能最终导致 癌症患者基因治疗的有用策略。