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联合治疗有反应，但患者会复发并最终变得难以治疗。因此，改善 CLL 化学免疫疗法的反应是当务之急，人们对可以增强这种反应的新型治疗剂非常感兴趣。 Rituximab 可诱导 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。使用转基因小鼠模型在小鼠淋巴细胞中过度表达 TCL-1 导致 AKT 激活并发展为类似于人类 CLL 的小鼠白血病。 TCL-1 在人类 CLL 细胞中过度表达，这为实验室和临床研究提供了动力，以减少受 TCL-1 影响的 TCL-1 和激酶（如 AKT）。研究药物 17-烯丙氨基-17-去甲氧基格尔德霉素 (17-AAG) 通过抑制伴侣蛋白 Hsp90 来消耗 AKT，该蛋白通常保护 AKT 免受蛋白酶体降解。在我们实验室的临床前研究中，17-AAG 下调 CLL 细胞中的 AKT，并且将 CLL 细胞暴露于利妥昔单抗和 17-AAG 会导致比单独使用任一药物所实现的更大的细胞凋亡。该拨款的具体目标 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。具体目标 2 是检查 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目标调节的关系。具体来说，我们将检查 17-AAG 对 PDK1/AKT/TCL-1 通路和其他依赖于 Hsp90 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，以及氟达拉滨和利妥昔单抗同时给药是否会增加对 17-AAG 作为单一药物的细胞凋亡反应。

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.