Multireceptor targeting of glioblastoma.
Multireceptor targeting of glioblastoma.
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DOI：
10.1093/noajnl/vdaa107
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Debinski W
中科院分区：
文献类型：
--
作者：
Sharma P;Sonawane P;Herpai D;D'Agostino R;Rossmeisl J;Tatter S;Debinski W
胶质母细胞瘤（GBM）的治疗在医学上仍然是一个未满足的需求。特别是针对GBM复杂性和异质性的新疗法是必要的。为此，我们一次靶向4个肿瘤相关受体，这些受体几乎跨越了所有的GBM微环境，包括大块肿瘤细胞、浸润性肿瘤细胞、新生血管和肿瘤浸润细胞，用一种药物递送细胞毒性负荷。我们设计了一种名为QUAD的多价配体载体蛋白，该蛋白能够结合以下4种gbm相关受体：IL-13RA2、EphA2、EphA3和EphB2。我们将QUAD与修饰的细菌毒素PE38QQR结合，并在体外和体内进行了测试。QUAD变体保留了4种受体各自配体的功能特征。QUAD 3.0变异偶联物对GBM细胞具有高度的细胞毒性，但在小鼠中无毒，并且偶联物对自发性GBM犬表现出很强的抗肿瘤作用。QUAD在很大程度上解决了肿瘤内和肿瘤间异质性的问题，同时，它通过肿瘤中过度表达的多个受体靶向GBM中几个病理生理上重要的肿瘤区室，从而实现我们所谓的“分子切除”。基于quad的靶向药物需要进一步的前期和临床开发。
Treatment for glioblastoma (GBM) remains an unmet need in medicine. Novel therapies that address GBM complexity and heterogeneity in particular are warranted. To this end, we target 4 tumor-associated receptors at a time that span virtually all of the GBM microenvironment including bulk tumor cells, infiltrating tumor cells, neovasculature, and tumor-infiltrating cells with one pharmaceutical agent delivering a cytotoxic load. We engineered multivalent ligand-based vector proteins termed QUAD with an ability to bind to 4 of the following GBM-associated receptors: IL-13RA2, EphA2, EphA3, and EphB2. We conjugated QUAD with a modified bacterial toxin PE38QQR and tested it in vitro and in vivo. The QUAD variants preserved functional characteristics of the respective ligands for the 4 receptors. The QUAD 3.0 variant conjugate was highly cytotoxic to GBM cells, but it was nontoxic in mice, and the conjugate exhibited strong antitumor effect in a dog with spontaneous GBM. The QUAD addresses, to a large extent, the issues of intra- and intertumoral heterogeneity and, at the same time, it targets several pathophysiologically important tumor compartments in GBM through multiple receptors overexpressed in tumors allowing for what we call “molecular resection.” QUAD-based targeted agents warrant further pre- and clinical development.
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影响因子：
7.2
作者：
Lisabeth EM;Falivelli G;Pasquale EB
通讯作者：
Pasquale EB
影响因子：
50.3
作者：
Binda E;Visioli A;Giani F;Lamorte G;Copetti M;Pitter KL;Huse JT;Cajola L;Zanetti N;DiMeco F;De Filippis L;Mangiola A;Maira G;Anile C;De Bonis P;Reynolds BA;Pasquale EB;Vescovi AL
通讯作者：
Vescovi AL
DOI：
10.15586/codon.glioblastoma.2017.ch18
发表时间：
2017-01-01
期刊：
GLIOBLASTOMA
影响因子：
--
作者：
Elenes, Egleide Y.;Rylander, Christopher G.
通讯作者：
Rylander, Christopher G.
影响因子：
3.7
作者：
Brown CE;Warden CD;Starr R;Deng X;Badie B;Yuan YC;Forman SJ;Barish ME
通讯作者：
Barish ME
影响因子：
3.7
作者：
Debinski W;Dickinson P;Rossmeisl JH;Robertson J;Gibo DM
通讯作者：
Gibo DM