Clinical Activity of 17-AAG in Lymphoma

描述（由申请人提供）：热休克蛋白(HSP)-90是一种细胞内蛋白，伴随几种对肿瘤过程很重要的癌蛋白，使其成为癌症治疗的一个有希望的分子靶点。HSP-90维持参与调节细胞存活、增殖和凋亡的几种关键癌蛋白的构象、稳定性和功能。与正常组织相比，包括淋巴瘤细胞在内的几种癌症类型表达高水平的HSP-90。17-AAG是格尔达霉素的一种小分子类似物，特异性结合并抑制HSP-90的功能，导致其客户癌蛋白如AKT、突变型p53、cyclin D1、Raf等参与细胞信号传导、存活和增殖的客户蛋白降解。17-AAG在临床前模型中显示出对几种实体瘤和白血病细胞的抗增殖活性，i期研究表明其在癌症患者中的安全性。然而，17-AAG在非霍奇金淋巴瘤（NHL）和霍奇金淋巴瘤（HL）中的活性尚不清楚。我们和其他人最近证明了热蛋白90在淋巴瘤细胞中大量表达。此外，我们的初步数据表明，17-AAG可以以剂量和时间依赖性的方式诱导几种NHL和HL细胞系的凋亡。在分子水平上，我们的初步数据表明，17-AAG降低了淋巴瘤细胞中关键存活蛋白和细胞周期蛋白的含量，包括AKT、ERK和cyclin D1；激活了内在半胱天冬酶途径。这些良好的体外抗肿瘤活性在套细胞淋巴瘤（MCL）、间变性大细胞淋巴瘤（ALCL）和HL细胞系中均有观察到。在此背景下，我们启动了17-AAG在复发性淋巴瘤患者中的i期研究。本提案的目的是评估17-AAG治疗复发难治性NHL和经典HL患者的疗效和安全性。在Aim 1中，我们建议在一项由ctep赞助的多中心ii期临床试验中检测17-AAG的活性，该试验针对复发和难治性MCL、ALCL和经典HL患者。在Aim 2中，我们提议评估17-AAG对17-AAG治疗患者原发性淋巴瘤细胞中选定分子靶点的生物学效应。在Aim 3中，我们将把17-AAG的生物学效应与复发MCL、ALCL和HL患者的临床反应联系起来。

DESCRIPTION (provided by applicant): Heat shock protein (HSP)-90 is an intracellular protein that chaperons several client oncoproteins important for the neoplastic process, making it a promising molecular target for cancer therapy. HSP-90 maintains the conformation, stability, and function of several critical client oncoproteins involved in regulating cell survival, proliferation, and apoptosis. Several cancer types, including lymphoma cells, have been shown to express high levels of HSP-90 compared with normal tissue. 17-AAG, a small molecule analog of geldanamycin, binds specifically and inhibits HSP-90 function, causing degradation of its client oncoproteins such as AKT, mutant p53, cyclin D1, Raf and other client proteins that are involved in cell signaling, survival, and proliferation. 17-AAG has demonstrated anti proliferative activity against several solid tumor and leukemia cells in preclinical models, and phase-l studies have demonstrated its safety in patients with cancer. However, the activity of 17-AAG in non-Hodgkin's lymphoma (NHL) and Hodgkin lymphoma (HL) is not known. We and others have recently demonstrated that HSP-90 is abundantly expressed in lymphoma cells. Furthermore, our preliminary data demonstrated that 17-AAG can induce apoptosis in several NHL and HL cell lines in a dose and time-dependent manner. At the molecular level, our preliminary data demonstrated that 17-AAG decreased lymphoma cellular contents of critical survival and cell cycle proteins including AKT, ERK, and cyclin D1; and activated the intrinsic caspase pathway. These favorable in vitro anti-tumor activities were observed in mantle cell lymphoma (MCL), anaplastic large cell lymphoma (ALCL) and HL cell lines. With this background, we initiated a phase-lI study of 17-AAG in patients with relapsed lymphoma. The purpose of this proposal is to evaluate the efficacy and safety of 17-AAG in the treatment of patients with relapsed and refractory NHL and classical HL. In Aim 1, we propose to examine the activity of 17-AAG in a multi-center, CTEP-sponsored phase-ll clinical trial in patients with relapsed and refractory MCL, ALCL, and classical HL. In Aim 2, we propose to evaluate the biologic effect of 17-AAG on selected molecular targets in primary lymphoma cells obtained from patients treated with 17-AAG. In Aim 3 we will correlate the biologic effects of 17-AAG and clinical response in patients with relapsed MCL, ALCL, and HL.