A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma.
A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma.
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DOI：
10.1158/1078-0432.ccr-08-3303
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发表时间：
2009-06-01
期刊：
影响因子：
--
通讯作者：
Goydos JS
中科院分区：
文献类型：
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作者：
Yip D;Le MN;Chan JL;Lee JH;Mehnert JA;Yudd A;Kempf J;Shih WJ;Chen S;Goydos JS
GRM 1在鼠黑素细胞中的异位表达导致转化为黑色素瘤的形式，并且超过60%的测试的人类黑色素瘤样品异位表达GRM 1。在体外刺激该受体导致激活的细胞外信号调节激酶（ERK）的上调。此外，与未处理的对照组相比，用利鲁唑（一种口服GRM 1阻断剂）治疗的黑素瘤异种移植模型显示肿瘤生长减少。我们现在已经完成了利鲁唑在黑色素瘤患者中的0期试验。参加这项试验的患者接受了治疗前活检，每天口服200 mg利鲁唑，持续14天，然后切除剩余的肿瘤。我们比较了治疗前和治疗后样本中pERK和pAKT的水平，并使用氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）扫描评估了治疗前和治疗后肿瘤的代谢活性。我们收集了12例患者，均表达GRM 1。我们发现，与4例（34%）患者的治疗前样本相比，治疗后肿瘤样本中的pAKT和/或pERK显著降低。这4例患者治疗后FDG-PET强度也显著降低。另外两名患者有临床反应，但没有相应的代谢反应;五名患者有相似的治疗前和治疗后FDG-PET扫描结果;一名患者有进展性疾病。我们的数据表明，利鲁唑的谷氨酸阻断可以抑制通过丝裂原活化蛋白激酶和磷脂酰肌醇3-激酶/AKT途径的信号传导，并抑制黑色素瘤的代谢活性。代谢型谷氨酸受体的异位表达可能在人黑色素瘤的发病机制中起重要作用，靶向该途径可能是一种有效的治疗方法。
Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal–regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma. Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and post-treatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease. Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy.