Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome.
Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome.
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DOI：
10.1056/nejmoa1113538
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发表时间：
2012-06-07
期刊：
影响因子：
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通讯作者：
Epstein EH Jr
中科院分区：
文献类型：
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作者：
Tang JY;Mackay-Wiggan JM;Aszterbaum M;Yauch RL;Lindgren J;Chang K;Coppola C;Chanana AM;Marji J;Bickers DR;Epstein EH Jr
hedgehog信号转导失调是基底细胞癌的关键分子异常。维莫德吉是一种新的口服刺猬通路抑制剂，在局部晚期和转移性基底细胞癌中产生客观反应。我们从2009年9月至2011年1月在三个临床中心的基底细胞痣综合征患者中进行了一项随机、双盲、安慰剂对照试验，测试了维莫德吉的抗基底细胞癌疗效。主要终点是3个月后，与安慰剂相比，vismodegib组符合手术切除条件的新基底细胞癌的发生率降低;次要终点包括现有基底细胞癌大小的减少。41例患者平均随访8个月（范围，1 - 15）登记后，与安慰剂组相比，维莫德吉组新发手术合格基底细胞癌的患者比例较低（每组每年2例对29例，P<0.001），以及它的大小（最长直径总和较基线的百分比变化）（−65% vs. − 11%，P = 0.003）。在一些患者中，所有基底细胞癌临床消退。在维莫德吉治疗期间没有肿瘤进展。接受维莫德吉治疗的患者通常会出现1级或2级不良事件，包括味觉丧失、肌肉痉挛、脱发和体重减轻。总体而言，54%的患者（26例中的14例）因不良事件而停止药物治疗。在1个月时，vismodegib的使用使基底细胞癌的hedgehog靶基因表达降低了90%（P<0.001），并减少了肿瘤细胞增殖，但凋亡不受影响。在83%的临床消退的基底细胞癌部位的活检样本中未检测到残留的基底细胞癌。维莫德吉降低基底细胞癌肿瘤负荷并阻断基底细胞痣综合征患者新基底细胞癌的生长与治疗相关的不良事件导致超过一半的治疗患者停药。（由Genentech和其他公司资助; ClinicalTrials.gov编号，NCT 00957229。
Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. We tested the anti–basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (−65% vs. −11%, P = 0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas. Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.)