WSD-0922, a novel brain-penetrant inhibitor of epidermal growth factor receptor, promotes survival in glioblastoma mouse models.
WSD-0922, a novel brain-penetrant inhibitor of epidermal growth factor receptor, promotes survival in glioblastoma mouse models.
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DOI：
10.1093/noajnl/vdad066
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发表时间：
2023-01
期刊：
影响因子：
--
通讯作者：
White FM
中科院分区：
文献类型：
--
作者：
Conage-Pough JE;Stopka SA;Oh JH;Mladek AC;Burgenske DM;Regan MS;Baquer G;Decker PA;Carlson BL;Bakken KK;Zhang J;Liu L;Sun C;Mu Z;Zhong W;Tran NL;Elmquist WF;Agar NYR;Sarkaria JN;White FM
虽然表皮生长因子受体（EGFR）是胶质母细胞瘤（GBM）中常见的致癌驱动因子，但治疗靶向这种蛋白质的努力在很大程度上是不成功的。本临床前研究评估了新型EGFR抑制剂WSD-0922。我们采用侧腹和原位患者来源的异种移植物模型来表征WSD-0922，并将其疗效与埃罗替尼（一种未能为GBM患者提供益处的强效EGFR抑制剂）进行比较。我们进行了长期生存研究，并从每种药物治疗的小鼠中收集了短期肿瘤，血浆和全脑样本。我们利用质谱法测量药物浓度和空间分布，并评估每种药物对受体活性和细胞信号网络的影响。在体外和体内模型中，WSD-0922与厄洛替尼一样有效地抑制EGFR信号传导。虽然WSD-0922在总浓度方面比厄洛替尼更具有CNS渗透性，但在原位模型中在肿瘤部位测量到两种药物的相当浓度，并且脑中游离WSD-0922的浓度显著低于游离厄洛替尼的浓度。在GBM 39模型中，与厄洛替尼相比，WSD-0922治疗提供了明显的存活优势，肿瘤生长受到显著抑制，大多数小鼠存活至研究结束。WSD-0922处理优先抑制几种蛋白质的磷酸化，包括与EGFR抑制剂抗性和细胞代谢相关的蛋白质。WSD-0922是GBM中EGFR的高效抑制剂，值得在临床研究中进一步评价。
Although the epidermal growth factor receptor (EGFR) is a frequent oncogenic driver in glioblastoma (GBM), efforts to therapeutically target this protein have been largely unsuccessful. The present preclinical study evaluated the novel EGFR inhibitor WSD-0922. We employed flank and orthotopic patient-derived xenograft models to characterize WSD-0922 and compare its efficacy to erlotinib, a potent EGFR inhibitor that failed to provide benefit for GBM patients. We performed long-term survival studies and collected short-term tumor, plasma, and whole-brain samples from mice treated with each drug. We utilized mass spectrometry to measure drug concentrations and spatial distribution and to assess the impact of each drug on receptor activity and cellular signaling networks. WSD-0922 inhibited EGFR signaling as effectively as erlotinib in in vitro and in vivo models. While WSD-0922 was more CNS penetrant than erlotinib in terms of total concentration, comparable concentrations of both drugs were measured at the tumor site in orthotopic models, and the concentration of free WSD-0922 in the brain was significantly less than the concentration of free erlotinib. WSD-0922 treatment provided a clear survival advantage compared to erlotinib in the GBM39 model, with marked suppression of tumor growth and most mice surviving until the end of the study. WSD-0922 treatment preferentially inhibited phosphorylation of several proteins, including those associated with EGFR inhibitor resistance and cell metabolism. WSD-0922 is a highly potent inhibitor of EGFR in GBM, and warrants further evaluation in clinical studies.
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影响因子：
4.8
作者：
Chattopadhyay, A;Vecchi, M;Carpenter, G
通讯作者：
Carpenter, G
DOI：
10.3390/molecules27030819
发表时间：
2022-01-26
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Amelia T;Kartasasmita RE;Ohwada T;Tjahjono DH
通讯作者：
Tjahjono DH
DOI：
10.1158/1078-0432.ccr-15-1677
发表时间：
2016-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ma Y;Tang N;Thompson RC;Mobley BC;Clark SW;Sarkaria JN;Wang J
通讯作者：
Wang J
影响因子：
9.9
作者：
Dittmann, Antje;Kennedy, Norman J.;White, Forest M.
通讯作者：
White, Forest M.
影响因子：
15.9
作者：
Marin, Bianca-Maria;Porath, Kendra A.;Sarkaria, Jann N.
通讯作者：
Sarkaria, Jann N.