Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells.
Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells.
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DOI：
10.3390/ph13120419
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发表时间：
2020-11-24
期刊：
影响因子：
--
通讯作者：
Cortopassi G
中科院分区：
文献类型：
--
作者：
Sandoval JA;Tomilov A;Datta S;Allen S;O'Donnell R;Sears T;Woolard K;Kovalskyy D;Angelastro JM;Cortopassi G
胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，诊断后平均生存期为15个月。GBM干细胞（GBMSC）抵抗标准治疗药物替莫唑胺，被认为是肿瘤抵抗的主要因素。哺乳动物雷帕霉素靶点复合物1 （mTORC1）调节细胞增殖，并已被其他人证明在GBMSC中活性降低。我们最近确定了一种新的基于哌嗪的人类安全脑渗透mtorc1特异性抑制剂的化学系列。我们通过生物层干涉法和场效应生物传感两种生物物理测量方法分析了哌嗪- mtor的结合强度，这两种生物物理测量方法相互证实并证明了结构-活性关系。由于mTORC1在人GBMSC中发生改变，并且mTORC1抑制剂已在先前的GBM临床试验中进行了测试，因此我们测试了结合最紧密的哌嗪类药物的杀伤能力，并观察到这些药物是有效的GBMSC杀手。GBMSCs对标准的替莫唑胺治疗有耐药性，但替莫唑胺与紧密结合的哌嗪、美氯嗪和氟桂利嗪联合使用大大提高了GBMSC的死亡率。最后，我们研究了已知影响线粒体和mTORC1代谢的idh1突变的GBMSC突变，并且紧密结合的美甲嗪在idh1突变的GBMSCs中引发了“合成致死性”。换句话说，idh1突变的GBMSC对替莫唑胺和美利嗪的联合使用表现出更大的敏感性。这些数据倾向于支持一种新的GBM临床策略，即在治疗GBM和idh1突变型GBM时，联合使用美利嗪或氟桂利嗪作为辅助治疗。
Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian target of rapamycin Complex 1 (mTORC1) regulates cell proliferation and has been shown by others to have reduced activity in GBMSC. We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed the piperazine-mTOR binding strength by two biophysical measurements, biolayer interferometry and field-effect biosensing, and these confirmed each other and demonstrated a structure–activity relationship. As mTORC1 is altered in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed that these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy, but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, and the tight-binding meclizine provoked ‘synthetic lethality’ in IDH1-mutant GBMSCs. In other words, IDH1-mutated GBMSC showed greater sensitivity to the coadministration of temozolomide and meclizine. These data tend to support a novel clinical strategy for GBM, i.e., the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM and IDH1-mutant GBM.
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影响因子：
16.6
作者：
Carbonneau, Melissa;Gagne, Laurence M.;Lalonde, Marie-Eve;Germain, Marie-Anne;Motorina, Alena;Guiot, Marie-Christine;Secco, Blandine;Vincent, Emma E.;Tumber, Anthony;Hulea, Laura;Bergeman, Jonathan;Oppermann, Udo;Jones, Russell G.;Laplante, Mathieu;Topisirovic, Ivan;Petrecca, Kevin;Huot, Marc-Etienne;Mallette, Frederick A.
通讯作者：
Mallette, Frederick A.
影响因子：
3.2
作者：
Machado, Luis Eduardo;Alvarenga, Arthur William;Maroso Hajj, Glaucia Noeli
通讯作者：
Maroso Hajj, Glaucia Noeli
影响因子：
11.4
作者：
Mallette, Frederick A.;Mattiroli, Francesca;Richard, Stephane
通讯作者：
Richard, Stephane
影响因子：
15.9
作者：
Ma, Daniel J.;Galanis, Evanthia;Sarkaria, Jann N.
通讯作者：
Sarkaria, Jann N.
影响因子：
64.8
作者：
Chen, Jian;Li, Yanjiao;Yu, Tzong-Shiue;McKay, Renee M.;Burns, Dennis K.;Kernie, Steven G.;Parada, Luis F.
通讯作者：
Parada, Luis F.