Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression.
Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression.
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DOI：
10.1016/j.tranon.2014.11.001
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发表时间：
2015-02
影响因子：
5
通讯作者：
Goydos, James S.
中科院分区：
文献类型：
--
作者：
Rosenberg, Stephen A.;Niglio, Scot A.;Salehomoum, Negar;Chan, Joseph L. -K.;Jeong, Byeong-Seon;Wen, Yu;Li, Jiadong;Fukui, Jami;Chen, Suzie;Shin, Seung-Shick;Goydos, James S.
我们的研究小组以前曾报道，大多数人类黑色素瘤（> 60%）表达代谢型谷氨酸受体1（GRM 1），谷氨酸释放抑制剂利鲁唑（目前用于治疗肌萎缩侧索硬化症的药物）可以诱导表达GRM 1的黑色素瘤细胞凋亡。我们的小组先前报道，在三维（3D）软琼脂集落测定中，体外利鲁唑治疗使野生型磷酸肌醇3-激酶（PI 3 K）通路激活的细胞生长减少80%。然而，含有PI 3 K途径的组成型激活突变（PTEN和NRAS突变）的黑素瘤细胞系显示，在存在利鲁唑的情况下，软琼脂中的集落形成仅减少35%至40%。在本研究中，我们继续了利鲁唑的临床前研究及其单独和与PI 3激酶通路抑制剂（AKT抑制剂API-2和哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂雷帕霉素）联合对黑色素瘤细胞的作用。我们在3D和2D系统和体内对各种黑色素瘤细胞系进行了这些组合疗法的建模。阿曲唑联合mTOR抑制在阻止黑色素瘤锚定非依赖性生长和异种移植肿瘤进展方面比单独使用任何一种药物更有效。与这种组合治疗相关的PI 3 K信号传导变化表明，细胞信号传导的3D（纳米培养）建模比单层模型更接近体内信号传导。阿曲唑联合mTOR抑制可有效阻止肿瘤细胞进展，与BRAF突变状态无关。这使得这种组合疗法成为转移性黑色素瘤患者的潜在可行替代方案，这些患者是BRAF WT，因此不适合维罗非尼治疗。
Our group has previously reported that the majority of human melanomas (> 60%) express the metabotropic glutamate receptor 1 (GRM1) and that the glutamate release inhibitor riluzole, a drug currently used to treat amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing melanoma cells. Our group previously reported that in vitro riluzole treatment reduces cell growth in three-dimensional (3D) soft agar colony assays by 80% in cells with wildtype phosphoinositide 3-kinase (PI3K) pathway activation. However, melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations) showed only a 35% to 40% decrease in colony formation in soft agar in the presence of riluzole. In this study, we have continued our preclinical studies of riluzole and its effect on melanoma cells alone and in combination with inhibitors of the PI3 kinase pathway: the AKT inhibitor, API-2, and the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. We modeled these combinatorial therapies on various melanoma cell lines in 3D and 2D systems and in vivo. Riluzole combined with mTOR inhibition is more effective at halting melanoma anchorage-independent growth and xenograft tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture) modeling of cell signaling more closely resembles in vivo signaling than monolayer models. Riluzole combined with mTOR inhibition is effective at halting tumor cell progression independent of BRAF mutational status. This makes this combinatorial therapy a potentially viable alternative for metastatic melanoma patients who are BRAF WT and are therefore ineligible for vemurafenib therapy.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
4.8
作者：
Marin, Yari E.;Namkoong, Jin;Chen, Suzie
通讯作者：
Chen, Suzie
影响因子：
45.3
作者：
Chapman, PB;Einhorn, LH;Kirkwood, JM
通讯作者：
Kirkwood, JM
影响因子：
6.2
作者：
Margolin, K;Longmate, J;Doroshow, JH
通讯作者：
Doroshow, JH
影响因子：
4.7
作者：
Marín, YE;Namkoong, J;Chen, S
通讯作者：
Chen, S