Sandoval Jose A, Tomilov Alexey, Datta Sandipan, Allen Sonia, O'Donnell Robert, Sears Thomas, Woolard Kevin, Kovalskyy Dmytro, Angelastro James M, Cortopassi Gino
Department of Molecular Biosciences, University of California Davis, Davis, CA 95616, USA.
Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA.
Pharmaceuticals (Basel). 2020 Nov 24;13(12):419. doi: 10.3390/ph13120419.
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.
胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，诊断后的平均生存期为15个月。胶质母细胞瘤干细胞（GBMSC）对标准治疗药物替莫唑胺具有抗性，被认为是肿瘤耐药的主要原因。哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）调节细胞增殖，其他人已证明其在GBMSC中的活性降低。我们最近发现了一系列新型的基于哌嗪的人脑渗透性mTORC1特异性抑制剂，且对人体安全。我们通过两种生物物理测量方法，即生物膜干涉术和场效应生物传感，测定了哌嗪与mTOR的结合强度，这两种方法相互印证，并证明了构效关系。由于mTORC1在人类GBMSC中发生改变，且mTORC1抑制剂已在先前的GBM临床试验中进行了测试，我们测试了结合力最强的哌嗪的杀伤效力，发现它们是强效的GBMSC杀手。GBMSC对标准治疗药物替莫唑胺疗法具有抗性，但补充了结合力强的哌嗪美克洛嗪和氟桂利嗪的替莫唑胺比单独使用替莫唑胺大大增强了GBMSC的死亡。最后，我们研究了已知会影响线粒体和mTORC1代谢的异柠檬酸脱氢酶1（IDH1）突变的GBMSC突变，结合力强的美克洛嗪在IDH1突变的GBMSC中引发了“合成致死性”。换句话说，IDH1突变的GBMSC对替莫唑胺和美克洛嗪联合给药表现出更高的敏感性。这些数据倾向于支持一种针对GBM的新型临床策略，即在治疗GBM和IDH1突变型GBM时联合使用美克洛嗪或氟桂利嗪作为辅助治疗。
