Clinical Activity of 17-AAG in Lymphoma

描述（由申请人提供）：热休克蛋白（HSP）-90是一种细胞内蛋白质，其陪伴几种对肿瘤过程重要的客户癌蛋白，使其成为癌症治疗的有希望的分子靶点。HSP-90维持参与调节细胞存活、增殖和凋亡的几种关键客户癌蛋白的构象、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已被证明表达高水平的HSP-90。17-AAG是格尔德霉素的小分子类似物，特异性结合并抑制HSP-90功能，导致其客户癌蛋白如AKT、突变型p53、细胞周期蛋白D1、Raf和其他参与细胞信号传导、存活和增殖的客户蛋白降解。17-AAG已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，并且I期研究已证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。我们和其他人最近已经证明，HSP-90是丰富的表达在淋巴瘤细胞。此外，我们的初步数据表明，17-AAG可以诱导几个NHL和HL细胞系的凋亡，在剂量和时间依赖性的方式。在分子水平上，我们的初步数据表明，17-AAG减少淋巴瘤细胞的关键生存和细胞周期蛋白，包括AKT，ERK和细胞周期蛋白D1的内容;并激活内在的caspase途径。在套细胞淋巴瘤（MCL）、间变性大细胞淋巴瘤（ALCL）和HL细胞系中观察到这些有利的体外抗肿瘤活性。在此背景下，我们启动了17-AAG在复发性淋巴瘤患者中的II期研究。本提案的目的是评价17-AAG治疗复发性和难治性NHL和经典HL患者的疗效和安全性。在目标1中，我们建议在复发性和难治性MCL、ALCL和经典HL患者中进行多中心、CTEP申办的II期临床试验，以检查17-AAG的活性。在目的2中，我们提出评估17-AAG对从用17-AAG治疗的患者获得的原发性淋巴瘤细胞中的选定分子靶标的生物学效应。在目标3中，我们将17-AAG的生物学效应与复发性MCL、ALCL和HL患者的临床应答相关联。

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.