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）：该项目解决了HSP90分子伴侣抑制剂的使用来促进癌细胞死亡。研究的重点是HSP90抑制剂与特定蛋白激酶抑制剂结合以促进凋亡的机制。苯甲喹啉甲霉素（包括GANamyin（GA））是抑制HSP90 ATPase活性的化合物，并通过泛素/蛋白酶体系统促进客户激酶和转录因子的降解。最近的临床试验与GA的衍生物为17-AAG，表明它的耐受性良好。此外，与健康组织的细胞相比，17-AAG似乎在促进肿瘤细胞死亡方面特别有效。 HSP90仅代表了在“靶向”化学治疗剂的新浪潮中已鉴定出的众多蛋白质之一。其他包括蛋白激酶（靶向治疗的原型），组蛋白脱乙酰基转移酶，蛋白酶体和抗凋亡蛋白。此外，有许多例子将针对两个靶标的疗法组合起来促进协同的癌细胞杀戮。这种协同作用的机制可能反映了信号通路通常组织到网络中的方式，其稳健特征可以承受单个组件的损失。由于HSP90在缓冲信号通路中具有一般作用，因此它可以为其他药物提供化学敏化细胞的基础。我们的研究是基于此基本原理。在第一个目的中，我们将根据初步研究来确定酪蛋白激酶II（CK2）和HSP90抑制剂的特异性促进癌细胞中的凋亡。我们将通过研究CK2和HSP90在细胞存活中具有收敛功能的途径来表征这种效应的机制。在AIM 2中，我们将确定其他蛋白激酶的功能损失会在HSP90抑制剂存在下促进凋亡，并表征其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细胞环境的调节以及B-RAF中的突变如何影响其伴侣依赖性。