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

描述（由申请人提供）：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的联合治疗有反应，但患者复发并最终变得难以治疗。因此，改善CLL对化学免疫疗法的反应是高度优先的，并且对可以增强这种反应的新型治疗剂有很大的兴趣。利妥昔单抗诱导CLL细胞凋亡，但同时通过磷酸化和激活AKT产生拮抗细胞存活信号。使用转基因小鼠模型在鼠淋巴细胞中过表达TCL-1导致AKT活化和类似于人CLL的鼠白血病的发展。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，以减少TCL-1和受TCL-1影响的激酶如AKT。研究药物17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）通过抑制分子伴侣蛋白Hsp 90来消耗AKT，Hsp 90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CLL细胞中的AKT，并且CLL细胞暴露于利妥昔单抗和17-AAG导致比单独使用任一种药物所实现的更大的凋亡。本基金的具体目标1是在氟达拉滨难治性CLL患者中进行17-AAG联合氟达拉滨和利妥昔单抗的I期剂量递增研究，以确定17-AAG作为单药和联合治疗的最大耐受剂量（MTD）、毒性特征和初步临床活性。具体目的2是检查17-AAG的药代动力学，以确定药代动力学参数如Cmax、Css和AUC与药效学靶点调节的关系。具体而言，我们将研究17-AAG对PDK 1/AKT/TCL-1通路和其他依赖于Hsp 90结合的蛋白质的影响。此外，我们将检查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增加对17-AAG作为单一药剂的细胞凋亡反应。

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.