Personalized medicine modality based on patient-derived xenografts from a malignant transformed GCTB harboring H3F3A G34W mutation.
Personalized medicine modality based on patient-derived xenografts from a malignant transformed GCTB harboring H3F3A G34W mutation.
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基于患者衍生的异种移植物的个性化医学模式，来自具有H3F3A G34W突变的恶性转化的GCTB。
DOI：
10.1016/j.jot.2021.04.004
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发表时间：
2021-07
影响因子：
6.6
通讯作者：
Zhengdong C
中科院分区：
文献类型：
--
作者：
Yafei J;Haoran M;Wenyan J;Linghang X;Kai T;Gangyang W;Zhuoying W;Jing H;Mengkai Y;Yujie T;Yingqi H;Zhengdong C
在几乎所有 GCTB 中都观察到了 H3F3A G43W 突变的功能，但其功能仍知之甚少。由于缺乏临床可用药物、有限的典型患者样本以及缺乏保真度临床前模型，恶性 GCTB 的突破一直受到阻碍。从恶性 GCTB 获得的肿瘤样本被植入免疫缺陷小鼠体内以产生 PDX。组织学检查和短串联重复序列（STR）用于遗传特征分析。选择表观遗传/转录靶向化合物库进行药物筛选。所选药物的体内作用在 PDX 模型中得到验证。我们利用复发性恶性GCTB标本建立了PDX模型，组织学检查和STR分析显示PDX及其相应的亲代患者具有相同的STR和组织学特征，表明具有共同的起源。 ITF-2357 是最重要的化合物，IC50 低于 0.1 uM。药物筛选和体内 PDX 验证的结果表明，ITF-2357 可能是一种有前途的靶向 H3F3A G34W 突变 MGCTB 的药物。我们的研究表明，PDX 模型保持了与原始患者相同的组织学和遗传特征。通过 ITF-2357 靶向 HDAC 可有效克服体外和体内的恶性 GCTB 进展。由于 PDX 保留了原发肿瘤的主要组织学和遗传特征，使其成为预测临床疗效的宝贵研究工具。在本研究中，我们首次建立了恶性GCTB PDX模型，这可能会进一步加速恶性GCTB的药物开发进展。 PDX模型是从恶性GCTB患者建立的。 PDC 和 PDX 维持与原始患者相同的肿瘤组织蛋白突变。 ITF-2357 在体外和体内抑制恶性 GCTB 进展。
The function of H3F3A G43W mutation, which has been observed in almost all GCTB, remains poorly characterized. Breakthrough in malignant GCTB has been trapped by the lack of clinical available drugs, limited canonical patient samples and paucity of fidelity preclinical models. Tumor samples obtained from a malignant GCTB was implanted in immunodeficient mice for the generation of PDX. Histological examination and short tandem repeat (STR) were used for inherited features analyses. An epigenetic/transcriptional targeted compound library was selected for drug screening. The in vivo effects of selected drug were validated in PDX model. We established the PDX model with recurrent malignant GCTB specimens, histological examination and STR analyses revealed that PDX and their corresponding parental patients shared the same STRs and histologic features, suggesting common origins. ITF-2357 was the most significant compound with an IC50 lower than 0.1 uM. The results of the drug screening and in vivo PDX validation demonstrated that ITF-2357 might be a promising drug targeted H3F3A G34W mutation MGCTBs. Our study demonstrates that PDX model maintained the same histologic and genetic features as those in the original patient. targeting HDAC through ITF-2357 effectively overcomes malignant GCTB progression in vitro and in vivo. As PDX retain the principal histologic and genetic characteristics of the primary tumors, mad it a valuable research tool in predictive clinical efficacy. In this study, we first established a malignant GCTB PDX model, which might further accelerate the progress of drug development in malignant GCTB. PDX model were established from a malignant GCTB patient. PDCs and PDX maintained same oncohiston mutations as those in the original patient. ITF-2357 inhibits malignant GCTB progression in vitro and in vivo.
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DOI：
10.1158/1078-0432.ccr-11-1488
发表时间：
2011-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Fleuren ED;Versleijen-Jonkers YM;van de Luijtgaarden AC;Molkenboer-Kuenen JD;Heskamp S;Roeffen MH;van Laarhoven HW;Houghton PJ;Oyen WJ;Boerman OC;van der Graaf WT
通讯作者：
van der Graaf WT
影响因子：
6.4
作者：
Lueke, Julian;von Baer, Alexandra;Barth, Thomas F. E.
通讯作者：
Barth, Thomas F. E.
影响因子：
30.8
作者：
Behjati, Sam;Tarpey, Patrick S.;Presneau, Nadege;Scheipl, Susanne;Pillay, Nischalan;Van Loo, Peter;Wedge, David C.;Cooke, Susanna L.;Gundem, Gunes;Davies, Helen;Nik-Zainal, Serena;Martin, Sancha;McLaren, Stuart;Goodie, Victoria;Robinson, Ben;Butler, Adam;Teague, Jon W.;Halai, Dina;Khatri, Bhavisha;Myklebost, Ola;Baumhoer, Daniel;Jundt, Gernot;Hamoudi, Rifat;Tirabosco, Roberto;Amary, M. Fernanda;Futreal, P. Andrew;Stratton, Michael R.;Campbell, Peter J.;Flanagan, Adrienne M.
通讯作者：
Flanagan, Adrienne M.
影响因子：
3.5
作者：
Gong, Lihua;Liu, Weifeng;Huang, XiaoYuan
通讯作者：
Huang, XiaoYuan
影响因子：
3.4
作者：
Zou, Changye;Lin, Tiao;Shen, Jingnan
通讯作者：
Shen, Jingnan