Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor
Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor
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DOI：
10.1056/nejmoa1411366
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发表时间：
2015-07-30
影响因子：
158.5
通讯作者：
Bollag, G.
中科院分区：
文献类型：
--
作者：
Tap, W. D.;Wainberg, Z. A.;Bollag, G.
背景：在大多数腱鞘巨细胞瘤中，集落刺激因子1（CSF 1）基因的表达升高。这一观察结果导致了针对CSF 1受体（CSF 1 R）的疗法的发现和临床开发。方法使用X射线共结晶学来指导我们的药物发现研究，我们产生了一种有效的、选择性的CSF 1 R抑制剂PLX 3397，它将激酶捕获在自抑制构象中。然后，我们进行了一项多中心的1期试验，分为两部分来分析这种化合物。在第一部分中，我们评估了实体瘤患者口服PLX 3397的剂量递增（剂量递增研究）。在第二部分中，我们在腱鞘巨细胞瘤患者的扩展队列（扩展研究）中评价了所选II期剂量的PLX 3397。评估入组患者的药代动力学和肿瘤反应，并进行CSF 1原位杂交以确认PLX 3397的作用机制，并且CSF 1表达模式与腱鞘巨细胞瘤的病理特征一致。选择的PLX 3397 II期剂量为1000 mg/天。在扩展研究中，12例腱鞘巨细胞瘤患者部分缓解，7例患者病情稳定。缓解通常发生在治疗的前4个月内，缓解的中位持续时间超过8个月。最常见的不良事件包括疲劳，头发颜色的变化，恶心，味觉障碍，眶周水肿;不良事件很少导致中断treatment.CONCLUSIONSTreatment的腱鞘巨细胞瘤与PLX 3397导致在肿瘤体积在大多数患者的长期回归。
BACKGROUNDExpression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R).METHODSUsing x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the auto-inhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor.RESULTSA total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment.CONCLUSIONSTreatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients.