IDH-mutant glioma: A new IDH1 inhibitor moves forward.
IDH-mutant glioma: A new IDH1 inhibitor moves forward.
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IDH 突变神经胶质瘤：一种新的 IDH1 抑制剂取得进展。
DOI：
10.1093/neuonc/noac275
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发表时间：
2023
期刊：
影响因子：
15.9
通讯作者：
Arrillaga-Romany,Isabel
中科院分区：
文献类型：
--
作者：
Miller,JulieJ;Arrillaga-Romany,Isabel
大约70%的低级别胶质瘤含有异柠檬酸脱氢酶1 （IDH1）突变，导致肿瘤代谢物d -2-羟基戊二酸（D-2-HG）的积累；这导致表观遗传失调、肿瘤发生和随后的克隆扩增。DS-1001是一种口服脑渗透突变型IDH1选择性抑制剂。这项首次人体研究调查了DS-1001的安全性、药代动力学、药效学和疗效。方法：这是一项多中心、开放标签、剂量递增、DS-1001治疗复发/进展性idh1突变（R132）胶质瘤（N = 47） （NCT03030066）的I期研究。DS-1001口服125-1400 mg，每日2次。剂量递增采用改进的连续重新评估方法。结果未达到最大耐受剂量。数据截止时，8名患者仍在继续治疗。大多数不良事件（ae）为1-2级。20例患者（42.6%）经历了至少1次3级AE。无4级或5级不良事件或严重药物相关不良事件报告。常见的不良反应为皮肤色素沉着、腹泻、瘙痒、脱发、关节痛、恶心、头痛、皮疹和皮肤干燥。强化肿瘤客观有效率为17.1%，非强化肿瘤客观有效率为33.3%。增强和非增强胶质瘤组的中位无进展生存期分别为10.4个月（95%置信区间[CI]， 6.1至17.7个月）和未达到（95% CI， 24.1至未达到）。与研究前存档的样本相比，7个接受治疗的脑肿瘤样本的D-2-HG含量显著降低。结论sds -1001耐受性好，脑内分布良好。复发/进行性idh1突变胶质瘤患者对治疗有反应。DS-1001在化疗和radiotherapy-naïve idh1突变的WHO 2级胶质瘤患者中的研究正在进行中（NCT04458272）。
BackgroundApproximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001.MethodsThis was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method.ResultsThe maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples.ConclusionsDS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).
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胰岛素刺激骨骼肌中α-（甲基）氨基异丁酸的摄取。
影响因子：
4.1
作者：
A. Gumà;X. Testar;M. Palacín;A. Zorzano
通讯作者：
A. Zorzano
L6 肌细胞氨基酸转运的调节： I. 氨基酸剥夺对转运系统 a 的刺激
影响因子：
5.6
作者：
W. Logan;A. Klip;E. Gagalang
通讯作者：
E. Gagalang
运动后肌肉α-氨基异丁酸转运：胰岛素增强刺激。
DOI：
10.1152/ajpendo.1985.248.5.e546
发表时间：
1985
期刊：
The American journal of physiology
影响因子：
--
作者：
Zorzano,A;Balon,TW;Garetto,LP;Goodman,MN;Ruderman,NB
通讯作者：
Ruderman,NB
运输特异性双环氨基酸在大鼠中的行为。
DOI：
10.1016/s0021-9258(18)91790-4
发表时间：
1969
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
H. Christensen;A. Cullen
通讯作者：
A. Cullen
大鼠骨骼肌中α-氨基异丁酸转运的特征。
DOI：
10.1042/bj2210071
发表时间：
1984
期刊：
The Biochemical journal
影响因子：
--
作者：
S. E. Lewis;D. Goldspink
通讯作者：
D. Goldspink