CCNY/MSK Cancer Center Partnership, Training and Community Outreach

CCNY/MSK 癌症中心合作、培训和社区外展

• 批准号: 7595293
• 负责人: KAREN HUBBARD
• 金额: $ 162.23万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595293
• 关键词: CCNY; MSK; Cancer; Center; Partnership

DESCRIPTION (provided by applicant): This project addresses the use of Hsp90 molecular chaperone -inhibitors to promote cancer cell death. The studies are focused on the mechanisms by which Hsp90 inhibitors synergize when combined with specific protein kinase inhibitors to promote apoptosis. Benzoquinoid ansamycins, including geldanamyin (GA), are compounds that inhibit Hsp90's ATPase activity and promote degradation of client kinases and transcription factors via the ubiquitin/proteasome system. Recent clinical trials with a derivative of GA, 17-AAG, showed that it is well tolerated. Furthermore, 17-AAG appears to be especially effective in promoting death of tumor cells compared with cells from healthy tissue. Hsp90 represents only one of many proteins that have been identified in a new wave of 'targeted' chemotherapeutics. Others include protein kinases (the prototype of targeted therapy), histone deacetyltransferases, the proteasome and anti-apoptotic proteins. In addition, there are many examples where combining therapies towards two targets promotes synergistic cancer cell killing. The mechanisms underlying this synergy likely reflects the way signaling pathways in general are organized into networks, whose robust character can withstand loss of a single component. Since Hsp90 has a general role in buffering signaling pathways, it could provide a basis for chemosensitizing cells to other drugs. Our studies are based on this rationale. In the first aim we will determine the specificity with which casein kinase II (CK2) and Hsp90 inhibitors promote apoptosis in cancer cells, based on preliminary studies. We will characterize the mechanisms of this effect by investigating pathways where CK2 and Hsp90 have a convergent function in cell survival. In aim 2, we will identify additional protein kinases whose loss of function promotes apoptosis in the presence of Hsp90 inhibitors and characterize their roles in cell survival. Finally, we will examine how Akt sensitivity to Hsp90 inhibitors is modulated by cellular environment and how mutation in B-Raf affects its chaperone-dependence.

描述（由申请人提供）：该项目致力于使用 Hsp90 分子伴侣抑制剂来促进癌细胞死亡。这些研究的重点是 Hsp90 抑制剂与特定蛋白激酶抑制剂联合使用时协同促进细胞凋亡的机制。苯醌类安沙霉素，包括格尔德霉素 (GA)，是抑制 Hsp90 ATP 酶活性并通过泛素/蛋白酶体系统促进客户激酶和转录因子降解的化合物。最近对 GA 衍生物 17-AAG 进行的临床试验表明，它具有良好的耐受性。此外，与健康组织的细胞相比，17-AAG 在促进肿瘤细胞死亡方面似乎特别有效。 Hsp90 仅代表新一波“靶向”化疗中已发现的众多蛋白质中的一种。其他包括蛋白激酶（靶向治疗的原型）、组蛋白脱乙酰转移酶、蛋白酶体和抗凋亡蛋白。此外，有许多例子表明，针对两个靶点的联合疗法可促进协同杀死癌细胞。这种协同作用背后的机制可能反映了信号通路一般组织成网络的方式，其强大的特性可以承受单个组件的损失。由于 Hsp90 在缓冲信号通路中具有普遍作用，因此它可以为细胞对其他药物的化学增敏提供基础。我们的研究就是基于这个道理。第一个目标是，我们将根据初步研究确定酪蛋白激酶 II (CK2) 和 Hsp90 抑制剂促进癌细胞凋亡的特异性。我们将通过研究 CK2 和 Hsp90 在细胞存活中具有聚合功能的途径来表征这种效应的机制。在目标 2 中，我们将鉴定其他蛋白激酶，这些蛋白激酶的功能丧失会在 Hsp90 抑制剂存在的情况下促进细胞凋亡，并表征它们在细胞存活中的作用。最后，我们将研究 Akt 对 Hsp90 抑制剂的敏感性如何受到细胞环境的调节，以及 B-Raf 的突变如何影响其伴侣依赖性。