Heat shock protein 90 as modulator of tumor cell survival

热休克蛋白 90 作为肿瘤细胞存活的调节剂

• 批准号: 6563980
• 负责人: LUKE J WHITESELL
• 金额: $ 29.68万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563980
• 关键词: SCID mouse; antineoplastics; cell growth regulation; clinical research; clinical trial phase I; drug design /synthesis /production; drug screening /evaluation; flow cytometry; heat shock proteins; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplastic growth; patient oriented research; polymerase chain reaction; protein binding; technology /technique development; time resolved data

Description (provided by applicant) The signal transduction pathways which control tumor Cell survival provide an attractive, rational target for the development of new anticancer agents. A particularly effective approach to inhibiting these pathways could be provided by drugs which alter the function of heat shock protein 90 (Hsp 90). This ubiquitously expressed molecular chaperone is not mutated in cancer. Instead, it appears to play an essential role in promoting minor cell survival by enhancing the stability and activity of multiple growth factor receptors, kinases and transcription factors. Although an attractive target conceptually, Hsp 90 function has never before been exploited therapeutically. As a result, the best manner in which to administer and evaluate novel Hsp 90-binding drugs such as 17-Nallylamino-17-demethoxygeldanamycin (hAAG) and chlorobiocin remains largely unknown. To address these issues, this project seeks to validate Hsp 90 as a useful chemotherapeutic target by defining practical, predictive molecular endpoints for assessment of drug action in cancer patients. The hypothesis to be tested is that the anticancer activity of Hsp 90-binding drugs results, at least in part, from the alterations in tumor cell survival signaling pathways which they induce. To test this hypothesis, the following experimental plan is proposed: 1. To develop new molecular assays based on innovative technologies such as laser scanning cytometry and real time PCR to measure drug-induced alterations in the very limited amounts of tumor and normal tissue which can realistically be obtained from patients. 2. To apply the assays developed in vitro to quantitate drug-induced alterations of specific molecular endpoints in normal and tumor tissues harvested from mice. 3. To correlate anti-tumor responses in cancer patients receiving Hsp 90- binding drugs with alterations in molecular endpoints and the results of non-invasive imaging procedures. Overall, the goal is to generate an understanding of how best to administer and measure the effects of both Hsp 90-binding drugs and molecularly targeted therapeutics in general. The insights gained are expected to contribute to significant improvements in the prevention and cure of cancer.

说明（申请人提供） 控制肿瘤细胞存活的信号转导途径提供了一个 有吸引力的，合理的新抗癌药物的发展目标。一 可以提供抑制这些途径的特别有效的方法 通过改变热休克蛋白90（Hsp 90）的功能的药物。这 普遍表达的分子伴侣在癌症中没有突变。相反地， 它似乎在促进小细胞存活方面发挥重要作用， 增强多种生长因子受体的稳定性和活性， 激酶和转录因子。虽然在概念上是一个有吸引力的目标， 热休克蛋白90的功能以前从未被用于治疗。因此，在本发明中， 给药和评估新型Hsp 90结合药物的最佳方式 如17-甲烯丙基氨基-17-去甲氧基格尔德霉素（hAAG）和氯霉素 仍然是未知的。为了解决这些问题，本项目力求 通过定义实际的， 用于评估癌症中药物作用的预测性分子终点 患者有待检验的假设是，热休克蛋白的抗癌活性 90-结合药物的结果，至少部分来自肿瘤细胞的改变， 它们诱导的生存信号通路。为了验证这一假设， 提出如下实验方案： 1.基于创新技术开发新的分子检测方法， 激光扫描细胞术和真实的时间PCR来测量药物诱导的改变 在非常有限的数量 肿瘤组织和正常组织，这可以从病人实际获得。 2.应用体外开发的测定法定量药物诱导的 正常和肿瘤组织中特异性分子终点的改变 从小鼠身上获得。 3.为了将接受热休克蛋白90的癌症患者的抗肿瘤反应与接受热休克蛋白90的癌症患者的抗肿瘤反应相关联， 结合药物与分子终点的改变和非侵入性的结果， 成像程序。 总的来说，目标是了解如何最好地管理 并测量Hsp 90结合药物和分子靶向药物的作用， 一般的治疗。所获得的见解预计将有助于 在癌症的预防和治疗方面取得了重大进展。