Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma.
Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma.
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DOI：
10.1158/1078-0432.ccr-08-1002
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发表时间：
2008-12-15
期刊：
影响因子：
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通讯作者：
Chapman PB
中科院分区：
文献类型：
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作者：
Solit DB;Osman I;Polsky D;Panageas KS;Daud A;Goydos JS;Teitcher J;Wolchok JD;Germino FJ;Krown SE;Coit D;Rosen N;Chapman PB
丝裂原活化蛋白激酶(MAPK)通路和磷脂酰肌醇3-激酶/AKT通路的激活似乎对黑色素瘤的增殖至关重要。这些通路的组成部分是热休克蛋白90(HSP90)的客户蛋白，这表明抑制HSP90可能具有显著的抗黑色素瘤作用。我们在黑色素瘤患者中使用HSP90抑制剂17-烯丙氨基-17-去甲氧基格尔达那霉素(17-AAG)进行了II期试验。主要终点是临床反应和治疗是否抑制MAPK通路活性。有可测量疾病的黑色素瘤患者根据他们的肿瘤是否含有V600E BRAF突变进行分层。静脉注射HSP90抑制剂17-AAG。每周1次，共6周，450 mg/m2。于注射前及注射17-AAG后18~50小时取肿瘤活检标本，快速冷冻保存。15名可评估的患者接受了治疗；9名患者患有BRAF突变，6名患者为野生型。没有观察到客观的反应。肿瘤活检组织的Western印迹分析显示，治疗后活检组织中HSP70的表达增加，细胞周期蛋白D1的表达降低，但对RAF激酶或磷酸化细胞外信号调节激酶的表达没有显著影响。用V600E BRAF突变特异性聚合酶链式反应分析血浆对预测肿瘤DNA测序结果的敏感性为86%，特异性为67%。在17-AAG的剂量和方案中，17-AAG对RAF激酶表达的影响是短暂的，没有看到客观的抗黑色素瘤反应。未来的黑色素瘤试验应该集中在一种更有效的HSP90抑制剂或一种可以长期给药的配方上，以更长时间地抑制MAPK途径。
Activation of the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase/AKT pathway seems to be critical for melanoma proliferation. Components of these pathways are client proteins of heat-shock protein 90 (hsp90), suggesting that inhibition of hsp90 could have significant antimelanoma effects. We conducted a phase II trial using the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in melanoma patients. The primary end points were clinical responses and whether treatment inhibited MAPK pathway activity. Melanoma patients with measurable disease were stratified on the basis of whether or not their tumor harbored a V600E BRAF mutation. The hsp90 inhibitor 17-AAG was administered i.v. once weekly ×6 weeks at 450 mg/m2. Tumor biopsies were obtained pretreatment and 18 to 50 hours after the first dose of 17-AAG, and were snap-frozen. Fifteen evaluable patients were treated; nine had BRAF mutations and six were wild-type. No objective responses were observed. Western blot analysis of tumor biopsies showed an increase in hsp70 and a decrease in cyclin D1expression in the posttreatment biopsies but no significant effect on RAF kinases or phospho - extracellular signal-regulated kinase expression. Plasma analyzed by mutant-specific PCR for V600E BRAF showed 86% sensitivity and 67% specificity in predicting tumor DNA sequencing results. At this dose and schedule of 17-AAG, the effects of 17-AAG on RAF kinase expression were short-lived, and no objective antimelanoma responses were seen. Future trials in melanoma should focus on a more potent hsp90 inhibitor or a formulation that can be administered chronically for a more prolonged suppression of the MAPK pathway.