CCNY/MSK Cancer Center Partnership, Training and Community Outreach

描述（由申请人提供）：该项目旨在使用Hsp 90分子伴侣抑制剂促进癌细胞死亡。这些研究主要集中在Hsp 90抑制剂与特异性蛋白激酶抑制剂联合作用促进细胞凋亡的机制上。苯醌类安莎霉素（Benzoquinoid ansamycins），包括格尔德霉素（geldanamyin，GA），是通过泛素/蛋白酶体系统抑制热休克蛋白90的ATP酶活性并促进客户激酶和转录因子降解的化合物。最近用GA的衍生物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。Hsp 90只是在新一波“靶向”化疗药物中发现的许多蛋白质之一。其他包括蛋白激酶（靶向治疗的原型），组蛋白脱乙酰转移酶，蛋白酶体和抗凋亡蛋白。此外，有许多实例表明，针对两个靶点的联合治疗促进了协同癌细胞杀伤。这种协同作用的机制可能反映了信号通路通常被组织成网络的方式，其强大的特性可以承受单个组件的损失。由于Hsp 90在缓冲信号通路中具有普遍作用，因此它可以为其他药物的化学增敏细胞提供基础。我们的研究正是基于这一理论。在第一个目标中，我们将确定酪蛋白激酶II（CK 2）和Hsp 90抑制剂促进癌细胞凋亡的特异性，基于初步研究。我们将通过研究CK 2和Hsp 90在细胞存活中具有会聚功能的途径来表征这种效应的机制。在目标2中，我们将确定额外的蛋白激酶，其功能丧失促进细胞凋亡的存在下的热休克蛋白90抑制剂和表征其在细胞存活中的作用。最后，我们将研究Akt对Hsp 90抑制剂的敏感性如何受细胞环境的调节，以及B-Raf突变如何影响其分子伴侣依赖性。

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.