Laemmerer Anna, Lehmann Christian, Mayr Lisa, Bruckner Katharina, Gabler Lisa, Senfter Daniel, Meyer Philipp, Balber Theresa, Pirker Christine, Jaunecker Carola N, Kirchhofer Dominik, Vician Petra, Griesser Michelle, Spiegl-Kreinecker Sabine, Schmook Maria T, Traub-Weidinger Tatjana, Kuess Peter, Eckert Franziska, Federico Aniello, Madlener Sibylle, Stepien Natalia, Robl Bernhard, Baumgartner Alicia, Hainfellner Johannes A, Dieckmann Karin, Dorfer Christian, Roessler Karl, Corsini Nina S, Holzmann Klaus, Schmidt Wolfgang M, Peyrl Andreas, Azizi Amedeo A, Haberler Christine, Beck Alexander, Pfister Stefan M, Schueler Julia, Lötsch-Gojo Daniela, Knoblich Jürgen A, Berger Walter, Gojo Johannes
Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.
Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Neuro Oncol. 2025 Mar 7;27(3):811-827. doi: 10.1093/neuonc/noae228.
Diffuse hemispheric glioma, H3 G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of alpha-thalassemia/mental retardation syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these 2 oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization, and consequently validate a targeted therapy approach.
We characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP ribose polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modeling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with PARPi combination therapy.
We elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT-phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in significant tumor reduction.
Our preclinical and clinical data strongly support the further development of PARPi together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.
弥漫性半球胶质瘤，H3 G34R/V突变型（DHG-H3G34）的特点是预后差且缺乏有效的治疗选择。DHG-H3G34R进一步存在X连锁的α地中海贫血/智力迟钝综合征蛋白（ATRX）失活（DHG-H3G34R_ATRX），提示这两种致癌改变存在独特的相互作用。在本研究中，我们剖析了它们的细胞生物学相互作用，研究了对端粒稳定性的影响，并因此验证了一种靶向治疗方法。
我们对患者来源的原发性儿童高级别胶质瘤（pHGG）模型进行了端粒维持机制、DNA损伤应激（包括蛋白表达、pH2AX/Rad51病灶、细胞周期停滞）及其对聚ADP核糖聚合酶抑制剂（PARPi）联合用药敏感性的特征分析。使用人类诱导多能干细胞（iPSC）对该疾病进行建模。在鸡胚绒毛尿囊膜（CAM）和原位体内实验中研究了PARPi联合用药在体内的抗癌活性。最后，我们用PARPi联合疗法治疗了一名DHG-H3G34R_ATRX患者。
我们阐述了端粒的替代延长（ALT）是DHG-H3G34R_ATRX的一个关键特征。在iPSC中，H3G34R和ATRX缺失在ALT激活中也表现出明显的显性协同效应，iPSC内源性发挥端粒酶活性。在患者来源的DHG-H3G34R_ATRX模型和H3G34R+/ATRX- iPSC中，ALT表型均与基础DNA损伤应激增加相关，介导了对PARPi（他拉唑帕尼、尼拉帕尼）与拓扑异构酶-I抑制剂（拓扑替康、伊立替康）联合用药的协同敏感性。在首例病例中，用可穿透脑的PARP抑制剂尼拉帕尼和拓扑替康治疗一名DHG-H3G34R_ATRX患者，导致肿瘤显著缩小。
我们的临床前和临床数据有力地支持了PARPi与针对DHG-H3G34R_ATRX的DNA损伤应激诱导治疗方案的进一步开发。
