The CCNY/MSKCC Partnership for Research, Training and Outreach

描述（由申请人提供）：本项目研究利用Hsp90分子伴侣抑制剂促进癌细胞死亡。研究的重点是Hsp90抑制剂与特定蛋白激酶抑制剂联合促进细胞凋亡的机制。苯甲喹类ansamyins，包括geldanamyin (GA)，是抑制Hsp90的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的临床试验表明，它具有良好的耐受性。此外，与来自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只是在新一波“靶向”化疗中发现的许多蛋白质中的一种。其他包括蛋白激酶（靶向治疗的原型）、组蛋白去乙酰转移酶、蛋白酶体和抗凋亡蛋白。此外，还有许多针对两个靶点的联合治疗促进协同癌细胞杀伤的例子。这种协同作用的机制可能反映了信号通路一般组织成网络的方式，网络的健壮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，它可以为细胞对其他药物的化学致敏提供基础。我们的研究就是基于这个基本原理。在第一个目标中，我们将在初步研究的基础上确定酪蛋白激酶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作用的机制。在目标2中，我们将确定在Hsp90抑制剂存在下功能丧失促进细胞凋亡的其他蛋白激酶，并描述它们在细胞存活中的作用。最后，我们将研究细胞环境如何调节Akt对Hsp90抑制剂的敏感性，以及B-Raf突变如何影响其伴侣依赖性。

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.