Jackson Evangeline R, Duchatel Ryan J, Staudt Dilana E, Persson Mika L, Mannan Abdul, Yadavilli Sridevi, Parackal Sarah, Game Shaye, Chong Wai Chin, Jayasekara W Samantha Nilanthi, Le Grand Marion, Kearney Padraic S, Douglas Alicia M, Findlay Izac J, Germon Zacary P, McEwen Holly P, Beitaki Tyrone S, Patabendige Adjanie, Skerrett-Byrne David A, Nixon Brett, Smith Nathan D, Day Bryan, Manoharan Neevika, Nagabushan Sumanth, Hansford Jordan R, Govender Dinisha, McCowage Geoffrey B, Firestein Ron, Howlett Meegan, Endersby Raelene, Gottardo Nicholas G, Alvaro Frank, Waszak Sebastian M, Larsen Martin R, Colino-Sanguino Yolanda, Valdés-Mora Fatima, Rakotomalala Andria, Meignan Samuel, Pasquier Eddy, Andre Nicolas, Hulleman Esther, Eisenstat David D, Vitanza Nicholas A, Nazarian Javad, Koschmann Carl, Mueller Sabine, Cain Jason E, Dun Matthew D
The University of Newcastle, Callaghan, NSW, Australia.
Children's National Hospital, Washington, DC, United States.
Cancer Res. 2023 May 5;83(14):2421-37. doi: 10.1158/0008-5472.CAN-23-0186.
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.
弥漫性中线胶质瘤（DMG），包括弥漫性脑桥内在型胶质瘤（DIPG），是儿童癌症中最致命的类型。姑息性放疗是唯一已确立的治疗方法，患者的中位生存期为9至11个月。ONC201是一种多巴胺受体D2（DRD2）拮抗剂和ClpP激动剂，已在DMG中显示出临床前和初步临床疗效。然而，还需要进一步研究以确定DIPG对ONC201治疗的反应机制，并确定复发的基因组特征是否影响反应。通过系统生物学方法，我们发现ONC201引发线粒体蛋白酶ClpP的强效激动作用，以驱动电子传递链和三羧酸循环蛋白的蛋白水解。携带PIK3CA突变的DIPG对ONC201的敏感性增加，而携带TP53突变的DIPG则更具抗性。氧化还原激活的PI3K/Akt信号传导促进了代谢适应和对ONC201的敏感性降低，使用可穿透脑的PI3K/Akt抑制剂帕扎利西布可抵消这种作用。总之，这些发现与ONC201和帕扎利西布强大的抗DIPG/DMG药代动力学和药效学特性相结合，为正在进行的DIPG/DMG II期联合临床试验NCT05009992提供了理论依据。
