Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.
Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.
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DOI：
10.1158/1535-7163.mct-15-0815
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发表时间：
2016-06
影响因子：
5.7
通讯作者：
Raynaud FI
中科院分区：
文献类型：
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作者：
Ang JE;Pandher R;Ang JC;Asad YJ;Henley AT;Valenti M;Box G;de Haven Brandon A;Baird RD;Friedman L;Derynck M;Vanhaesebroeck B;Eccles SA;Kaye SB;Workman P;de Bono JS;Raynaud FI
磷脂酰肌醇-3-激酶（PI 3 K）在细胞代谢和癌症中起关键作用。使用基于质谱的代谢组学平台，我们发现，与非肿瘤对照相比，携带PTEN缺陷型肿瘤的小鼠中26种代谢物（包括氨基酸、酰基肉毒碱和磷脂酰胆碱）的血浆浓度降低，并且在给予I类PI 3 K抑制剂匹替利昔布（GDC-0941）后增加。这些候选代谢组学生物标志物在pictilisib的I期剂量递增临床试验中进行了评估。在患者中观察到22种血浆代谢产物的时间和剂量依赖性效应。这些变化超过基线变异性，在药物洗脱后消退，并在连续给药后重现。我们的研究提供了PI 3 K通路的调节与血浆代谢组学变化之间的联系，并证明血浆代谢组学是生物标志物评价的可行且有前途的策略。此外，我们的研究结果提供了额外的支持，胰岛素抵抗，支链氨基酸和相关代谢产物后PI 3 K抑制之间的关联。
Phosphoinositide-3-kinase (PI3K) plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non-tumor bearing controls and in addition were increased following dosing with Class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a Phase I dose-escalation clinical trial of pictilisib. Time- and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids and related metabolites following PI3K inhibition.