A Phase I Study of the AKT Inhibitor 17-AAG in CLL

描述(申请人提供)：虽然慢性淋巴细胞白血病(CLL)患者对氟达拉滨和利妥昔单抗联合治疗有反应，但患者会复发，最终变得难以治疗。因此，提高CLL对化学免疫治疗的反应是当务之急，人们对可能增强这种反应的新型治疗药物非常感兴趣。利妥昔单抗诱导CLL细胞凋亡，但同时通过磷酸化和激活AKT产生拮抗细胞生存信号。利用转基因小鼠模型在小鼠淋巴细胞中过表达TCL-1导致了AKT的激活和一种类似于人类CLL的小鼠白血病的发生。TCL-1在人CLL细胞中过表达，为实验室和临床研究提供了动力，以降低TCL-1和AKT等受TCL-1影响的激酶的表达。研究药物17-烯丙氨基-17-去甲氧基格尔达那霉素(17-AAG)通过抑制伴侣蛋白Hsp90来耗尽AKT，Hsp90通常保护AKT免受蛋白体降解。在我们实验室的临床前研究中，17-AAG下调了CLL细胞中AKT的表达，并且将CLL细胞暴露于利妥昔单抗和17-AAG中，导致了比单独使用这两种药物更大的细胞凋亡。这笔赠款的具体目标1是进行17-AAG与氟达拉滨和利妥昔单抗联合治疗难治性慢性淋巴细胞白血病患者的I期剂量递增研究，以确定17-AAG作为单一药物和联合治疗的最大耐受剂量(MTD)、毒性分布和初步临床活性。具体目的2是研究17-AAG的药代动力学，以确定Cmax、Css和AUC等药代动力学参数与药效学指标调节的关系。具体地说，我们将研究17-AAG对PDK1/AKT/TCL-1途径和其他依赖于Hsp90结合的蛋白质的影响。此外，我们还将研究17-AAG是否影响自发的、药物诱导的和利妥昔单抗诱导的细胞凋亡，以及同时给予氟达拉滨和利妥昔单抗是否会作为单一药物增加对17-AAG的凋亡反应。

DESCRIPTION (provided by applicant): While patients with chronic lymphocytic leukemia (CLL) respond to combined therapy with fludarabine and rituximab, patients relapse and eventually become refractory to treatment. Therefore, improving response to chemoimmunotherapy in CLL is a high priority, and there is great interest in novel therapeutic agents that may enhance this response. Rituximab induces apoptosis in CLL cells but concurrently generates an antagonizing cell survival signal by phosphorylating and activating AKT. Over-expression of TCL-1 in murine lymphocytes using a transgenic mouse model resulted in AKT activation and development of a murine leukemia similar to human CLL. TCL-1 is over-expressed in human CLL cells, providing an impetus for laboratory and clinical studies to target the reduction of TCL-1 and kinases such as AKT, which are influenced by TCL-1. The investigational drug 17-allylamino-17-demethoxygeldanamycin (17-AAG) depletes AKT by inhibiting the chaperone protein Hsp90, which normally protects AKT from proteosomal degradation. In preclinical studies in our laboratory, 17-AAG down-regulated AKT in CLL cells, and exposure of CLL cells to rituximab and 17-AAG resulted in greater apoptosis than that achieved by either agent alone. Specific Aim 1 of this grant is to perform a phase I dose escalation study of 17-AAG, combined with fludarabine and rituximab, in patients with fludarabine-refractory CLL, in order to determine the maximum tolerated dose (MTD), toxicity profile and preliminary clinical activity of 17-AAG as a single agent and in combination therapy. Specific Aim 2 is to examine the pharmacokinetics of 17-AAG to determine the relationship of pharmacokinetic parameters such as Cmax, Css and AUC to modulation of pharmacodynamic targets. Specifically, we will examine the effects of 17-AAG on the PDK1/AKT/TCL-1 pathway and other proteins dependent upon Hsp90 binding. In addition, we will examine whether 17-AAG affects spontaneous, drug-induced and rituximab-induced apoptosis, and whether concurrent administration of fludarabine and rituximab increases the apoptotic response to 17-AAG as a single agent.