GDP-bound Ras mutant RasN17N69 as a therapeutic agent

GDP 结合 Ras 突变体 RasN17N69 作为治疗剂

• 批准号: 6441406
• 负责人: Li-Hui Xu
• 金额: $ 11.64万
• 依托单位: ONCOIMMUNE, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-06 至 2003-03-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6441406
• 关键词: antineoplastics; athymic mouse; biological signal transduction; drug design /synthesis /production; drug screening /evaluation; guanine nucleotide binding protein; guanosine diphosphate; neoplastic cell; neoplastic transformation; oncogenes; phenotype; tissue /cell culture

DESCRIPTION (provided by applicant): The Ras oncogene is one of the most frequently mutated oncogenes in human cancer. Approximately 30 percent of human cancers contain activated Ras mutations. Extensive efforts have been made to identify Ras inhibitor as a putative cancer therapy with the most promising progress of farnesyl transferase inhibitor. Farnesylation of Ras is essential for its biological functions. However, many small GTPases, which play important roles in cellular functions, also require farnesylation or isoprenylation. Therefore, these inhibitors may have none specific effects due to inhibition of other small GTPases. A major long-term goal of OncoImmune is to develop therapeutic agents for treatment of cancers. The main goal of this proposal is to demonstrate that GDP-bound Ras mutant, RasN17N69, can be used to inhibit cancer cell growth in vitro and in vivo. This proposal is based on our novel observations that RasN17N69 inhibits cell transformation but not growth of normal cells. Furthermore, the proposal uses a new technology of protein transduction to test this hypothesis in vitro and in vivo. The following specific aims will be accomplished in this proposal. 1. To demonstrate that GDP-bound mutant RasN17N69 can suppress transforming phenotypes of tumor cells. 2. To provide evidence that RasN17N69 can inhibit tumor growth in animal model. PROPOSED COMMERCIAL APPLICATION: Cancer is one of the leading causes of mortality in the US. Approximately 30% of human cancers contain activating mutation of Ras. This project will provide critical information that RasN17N69 can be used in treatment of cancers containing Ras mutation. The proposal is based on a novel concept that the GDP-bound RasN17N69 can reverse transformation by oncogenic Ras mutation. The potential commercial application and therapeutic benefits are far reaching.

描述（由申请人提供）：Ras 癌基因是最常见的癌基因之一。 人类癌症中经常发生突变的癌基因。大约有30%的人类 癌症含有激活的 Ras 突变。已经做出了广泛的努力 确定 Ras 抑制剂是最有希望的假定癌症治疗方法 法呢基转移酶抑制剂的研究进展Ras 的法尼基化至关重要 因其生物学功能。然而，许多小型 GTPases 发挥着重要作用 细胞功能中的作用，也需要法尼基化或异戊二烯化。 因此，这些抑制剂可能由于抑制 其他小 GTPa 酶。 OncoImmune 的一个主要长期目标是开发 用于治疗癌症的治疗剂。该提案的主要目标是 证明 GDP 结合的 Ras 突变体 RasN17N69 可用于抑制 癌细胞在体外和体内的生长。这个建议是根据我们的小说改编的 RasN17N69 抑制细胞转化但不抑制细胞生长 正常细胞。此外，该提案还使用了蛋白质新技术 转导以在体外和体内检验这一假设。 本提案将实现以下具体目标。 1. 证明GDP结合突变体RasN17N69可以抑制转化 肿瘤细胞的表型。 2. 为RasN17N69在动物模型中抑制肿瘤生长提供证据。 拟议的商业应用：癌症是美国死亡的主要原因之一。 大约 30% 的人类癌症含有 Ras 激活突变。 该项目将提供RasN17N69可用于治疗含有Ras突变的癌症的关键信息。 该提案基于一个新概念，即 GDP 结合的 RasN17N69 可以通过致癌 Ras 突变逆转转化。 潜在的商业应用和治疗效益是深远的。