Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts.
Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts.
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DOI：
10.3390/cancers14225494
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发表时间：
2022-11-09
期刊：
影响因子：
5.2
通讯作者：
Horbinski C
中科院分区：
文献类型：
--
作者：
McCord M;Bartom E;Burdett K;Baran A;Eckerdt FD;Balyasnikova IV;McCortney K;Sears T;Cheng SY;Sarkaria JN;Stupp R;Heimberger AB;Ahmed A;James CD;Horbinski C
胶质母细胞瘤（GBM）是最常见和最具侵袭性的成人型弥漫浸润性胶质瘤。这些肿瘤总是对放射和替莫唑胺的标准治疗产生耐药性，导致复发和几乎总是致命的结果。这种复发的体内模型是有限的，复发性GBM的新疗法通常在未经治疗的临床前模型上进行测试，这些模型不能准确预测临床试验的结果。在小鼠中对未经治疗的肿瘤模型有效的实验性疗法通常无法在复发性、耐药性GBM患者中实现生存获益。在这项研究中，我们通过将GBM的患者来源的异种移植物（PDX）暴露于辐射和替莫唑胺来开发多种治疗抗性GBM模型。这些耐药PDX反映了患者复发性GBM的关键遗传和表型特征。这些PDX模型稳定且可扩展，可以作为在更准确地模拟一线治疗后复发的GBM的环境中测试新疗法的宝贵工具。成人型弥漫性浸润性胶质瘤，其中胶质母细胞瘤是最常见和最具侵袭性的，几乎总是在治疗后复发，并且是致命的。提高对胶质瘤中治疗驱动的肿瘤演变和获得性治疗耐药性的理解对于改善患者预后至关重要，但目前临床前研究中使用的大多数模型都是治疗初治肿瘤。在这里，我们描述了治疗抗性IDH野生型胶质母细胞瘤患者来源的异种移植物（PDX）的发展，通过原位移植的治疗幼稚的PDX在无胸腺裸鼠，并重复在体内暴露于治疗胶质母细胞瘤患者最常用的治疗方式：放疗和替莫唑胺化疗。替莫唑胺后PDX变得富含C>T转换突变，在DNA错配修复基因（特别是MSH6）中获得失活突变，并发生超突变。这样的替莫唑胺后PDX对另外的替莫唑胺具有抗性（中位生存期从亲本PDX中的80天降低至替莫唑胺抗性衍生物中的42天）。然而，替莫唑胺耐药PDX对洛莫司汀（也称为CCNU）敏感，洛莫司汀是一种亚硝基脲，通过与替莫唑胺不同的机制诱导肿瘤细胞凋亡。这些PDX模型模拟了在患者复发性GBM中观察到的变化，包括治疗驱动的肿瘤演变的关键特征。因此，这些模型可以作为有价值的工具，提高我们的理解和治疗复发性胶质瘤。
Glioblastoma (GBM) is the most common and aggressive adult-type diffusely infiltrating glioma. These tumors invariably develop resistance to standard treatment with radiation and temozolomide, leading to recurrence and almost always fatal outcomes. In vivo models of such recurrences are limited, and new therapies for recurrent GBM are usually tested on therapy-naïve preclinical models, which do not accurately predict outcomes in clinical trials. Experimental therapies which are effective against therapy-naïve tumor models in mice often fail to achieve survival benefit in patients with recurrent, therapy-resistant GBMs. In this study, we developed multiple treatment-resistant GBM models by exposing patient-derived xenografts (PDX) of GBM to radiation and temozolomide. These therapy-resistant PDX reflect key genetic and phenotypic features of recurrent GBM in patients. These PDX models are stable and expandable, and can serve as a valuable tool for testing new therapies in a setting that more accurately models GBM that recurs after front-line therapy. Adult-type diffusely infiltrating gliomas, of which glioblastoma is the most common and aggressive, almost always recur after treatment and are fatal. Improved understanding of therapy-driven tumor evolution and acquired therapy resistance in gliomas is essential for improving patient outcomes, yet the majority of the models currently used in preclinical research are of therapy-naïve tumors. Here, we describe the development of therapy-resistant IDH-wildtype glioblastoma patient-derived xenografts (PDX) through orthotopic engraftment of therapy naïve PDX in athymic nude mice, and repeated in vivo exposure to the therapeutic modalities most often used in treating glioblastoma patients: radiotherapy and temozolomide chemotherapy. Post-temozolomide PDX became enriched for C>T transition mutations, acquired inactivating mutations in DNA mismatch repair genes (especially MSH6), and developed hypermutation. Such post-temozolomide PDX were resistant to additional temozolomide (median survival decrease from 80 days in parental PDX to 42 days in a temozolomide-resistant derivative). However, temozolomide-resistant PDX were sensitive to lomustine (also known as CCNU), a nitrosourea which induces tumor cell apoptosis by a different mechanism than temozolomide. These PDX models mimic changes observed in recurrent GBM in patients, including critical features of therapy-driven tumor evolution. These models can therefore serve as valuable tools for improving our understanding and treatment of recurrent glioma.
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影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
从癌症中丧生（YLL）是人口负担的重要衡量标准，在分配研究基金时应考虑。
影响因子：
8.8
作者：
Burnet, NG;Jefferies, SJ;Benson, RJ;Hunt, DP;Treasure, FP
通讯作者：
Treasure, FP
DOI：
10.1093/noajnl/vdab045
发表时间：
2021-01
期刊：
Neuro-oncology advances
影响因子：
--
作者：
McCord M;Lukas RV;Amidei C;Demars N;Gelb A;Buck J;Sachdev S;Feldman A;Tate M;Dixit K;Brat DJ;Jennings L;Horbinski C
通讯作者：
Horbinski C
影响因子：
158.5
作者：
Hegi, ME;Diserens, A;Stupp, R
通讯作者：
Stupp, R
影响因子：
15.9
作者：
Hodges, Tiffany R.;Ott, Martina;Heimberger, Amy B.
通讯作者：
Heimberger, Amy B.