Phase I Trial of Bortezomib and Romidepsin in CLL and Small Cell Lymphoma

描述(申请人提供)：本实验室和其他实验室以前的研究已经证实，组蛋白脱乙酰酶抑制剂(HDACIs)和蛋白酶体抑制剂(如Bortezomib)相互作用，协同诱导恶性人类造血细胞的凋亡。在慢性淋巴细胞白血病(CLL)细胞中，协同作用的假设机制主要集中在Bortezomib介导的阻断HDACi诱导的relA乙酰化和激活规范的和替代的NF-：B通路，导致NF-：B依赖的生存蛋白(如BclXL和XIAP)的下调。最近，我们观察到，当在体外以极低的浓度(即每个浓度为3-5 nM)联合给药时，I类HDACi romidessin(去脂肽；FK228)与Bortezomib相互作用，在新鲜的原代CLL细胞和.CLL细胞系中诱导非常显著的凋亡。此外，这些事件与阻止罗米非菌素诱导的经典和替代的NF-：B通路的激活，下调依赖于NF-：B的蛋白BclXL和XIAP，以及诱导促凋亡蛋白Bim有关。我们现在建议通过进行I期试验来开始测试这些临床前发现的体内影响。这项建议的具体目的是：首先，确定波特佐米和罗米地平联合治疗慢性淋巴细胞性白血病/小淋巴细胞性淋巴瘤(CLL/SLL)的最大耐受量(MTD)；确定联合用药的安全性和毒性；并记录在剂量发现研究过程中观察到的联合用药的活性。其次，展示足够的技术来评估CLL细胞对联合用药的药效学反应，包括对规范的和替代的NF-：B途径(作为P100加工的标记)的激活的影响，对依赖于核因子：B的蛋白XIAP和BclXL的表达，以及促凋亡蛋白Bim的表达的影响；以及记录在剂量发现研究过程中观察到的药效反应。公共卫生相关性：我们实验室的研究表明，组蛋白去乙酰酶抑制剂罗米迪辛和蛋白酶体抑制剂在诱导原代慢性淋巴细胞性白血病(CLL)细胞死亡方面具有很强的相互作用。本研究的目的是确定慢性淋巴细胞性白血病/小细胞淋巴细胞性淋巴瘤(CLL/SLL)患者每周3次联合用药的最大耐受量(MTD)，以确定其安全性和毒性，并记录在剂量发现研究过程中观察到的联合用药的活性。此外，其目的是证明足够的技术来评估CLL细胞对组合的药效学反应，关于对规范的和替代的NF-：B途径的激活的影响，选择的NF：B依赖的蛋白的表达，以及促凋亡蛋白Bim的表达，并记录在剂量发现研究过程中观察到的药效学反应。这将使我们能够进行未来的试验，以确定这种新型药物组合在慢性淋巴细胞白血病或系统性红斑狼疮患者中的有效性，并解决我们临床前药效学观察的有效性。

DESCRIPTION (provided by applicant): Previous studies from this and other laboratories have established that histone deacetylase inhibitors (HDACIs) and proteasome inhibitors such as bortezomib interact synergistically to induce apoptosis in malignant human hematopoietic cells. In chronic lymphocytic leukemia (CLL) cells, postulated mechanisms of synergism have focused on bortezomib-mediated blockade of HDACI-induced RelA acetylation and activation of the canonical and alternative NF-:B pathways, resulting in down regulation of NF-:B-dependent survival proteins (e.g., Bcl-xL and XIAP). Very recently, we have observed that when co-administered in vitro at extremely low concentrations (i.e. 3-5 nM each), the Class I HDACI romidepsin (depsipeptide; FK228) interacts with bortezomib to induce very pronounced apoptosis in fresh primary CLL cells as well as .CLL cell lines. Furthermore, these events are associated with prevention of romidepsin-induced activation of the classical and alternative NF-:B pathways, down regulation of the NF-:B dependent proteins Bcl-xL and XIAP, and induction of the pro-apoptotic protein Bim. We now propose to begin testing the in vivo implications of these preclinical findings by conducting a Phase I trial. The specific aims of this proposal are: First, to determine the maximum tolerated dose (MTD) for the combination of bortezomib and romidepsin administered weekly x 3 every 4 weeks in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); to determine the safety and describe the toxicities of the combination; and to document activity of the combination observed in the course of the dose finding study. Second, to demonstrate adequate techniques for the assessment of pharmacodynamic responses of CLL cells to the combination with respect to effects on activation of the canonical and alternative NF-:B pathways (nuclear RelA and p52 as a marker of p100 processing), expression of the NF-:B-dependent proteins XIAP and Bcl-xL, and expression of the pro-apoptotic protein Bim; and to document pharmacodynamic responses observed in the course of the dose finding study. PUBLIC HEALTH RELEVANCE: Studies from our laboratory have shown a potent interaction between the histone deacetylase inhibitor romidepsin and the proteosome inhibitor in inducing cell death in primary chronic lymphocytic leukemia (CLL) cells. The purpose of this study is to determine the maximum tolerated dose (MTD) for the combination administered weekly x 3 every 4 weeks in patients with chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL), to determine the safety and describe the toxicities of the combination, and to document activity of the combination observed in the course of the dose finding study. Further, the purpose is to demonstrate adequate techniques for the assessment of pharmacodynamic responses of CLL cells to the combination with respect to effects on activation of the canonical and alternative NF-:B pathways, expression of selected NF-:B-dependent proteins, and expression of pro-apoptotic protein Bim, and to document pharmacodynamic responses observed in the course of the dose finding study. This will position us to perform future trials that will determine the effectiveness of this novel drug combination in patients with CLL or SLL and address the validity of our preclinical pharmacodynamic observations.