Bonner Erin R, Waszak Sebastian M, Grotzer Michael A, Mueller Sabine, Nazarian Javad
Center for Genetic Medicine, Children's National Health System, Washington, DC.
Institute for Biomedical Sciences, The George Washington University School of Medicine and Health Sciences, Washington, DC.
Neuro Oncol. 2021 Apr 12;23(4):542-556. doi: 10.1093/neuonc/noaa283.
ONC201 is the first member of the imipridone family of anticancer drugs to enter the clinic for the treatment of diverse solid and hematologic cancers. A subset of pediatric and adult patients with highly aggressive brain tumors has shown remarkable clinical responses to ONC201, and recently, the more potent derivative ONC206 entered clinical trials as a single agent for the treatment of central nervous system (CNS) cancers. Despite the emerging clinical interest in the utility of imipridones, their exact molecular mechanisms are not fully described. In fact, the existing literature points to multiple pathways (e.g. tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) signaling, dopamine receptor antagonism, and mitochondrial metabolism) as putative drug targets. We have performed a comprehensive literature review and highlighted mitochondrial metabolism as the major target of imipridones. In support of this, we performed a meta-analysis of an ONC201 screen across 539 human cancer cell lines and showed that the mitochondrial caseinolytic protease proteolytic subunit (ClpP) is the most significant predictive biomarker of response to treatment. Herein, we summarize the main findings on the anticancer mechanisms of this potent class of drugs, provide clarity on their role, and identify clinically relevant predictive biomarkers of response.
ONC201是进入临床用于治疗多种实体癌和血液系统癌症的咪吡酮类抗癌药物家族的首个成员。一部分患有高度侵袭性脑肿瘤的儿科和成年患者对ONC201表现出显著的临床反应，最近，更强效的衍生物ONC206作为单一药物进入了治疗中枢神经系统（CNS）癌症的临床试验。尽管临床上对咪吡酮类药物的效用兴趣日增，但其确切的分子机制尚未完全阐明。事实上，现有文献指出多种途径（如肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）信号传导、多巴胺受体拮抗作用和线粒体代谢）可能是药物靶点。我们进行了全面的文献综述，并强调线粒体代谢是咪吡酮类药物的主要靶点。为此，我们对539个人类癌细胞系进行的ONC201筛选进行了荟萃分析，结果表明线粒体酪蛋白水解蛋白酶蛋白水解亚基（ClpP）是治疗反应最显著的预测生物标志物。在此，我们总结了这类强效药物抗癌机制的主要发现，明确了它们的作用，并确定了临床上相关的反应预测生物标志物。
