Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

中文翻译：

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卡马替尼是 MET 融合驱动的儿童高级别胶质瘤的有效治疗方法，并与放射治疗具有协同作用


儿童型弥漫性高级别胶质瘤（pHGG）是儿童中最常见的恶性脑肿瘤，可细分为多种实体。激活 MET 受体酪氨酸激酶的融合基因通常出现在婴儿型半球神经胶质瘤 (IHG) 中，但也出现在其他 pHGG 中，并与毁灭性的发病率和死亡率相关。为了确定新的治疗方案，我们建立并表征了两种具有不同 MET 融合的新型原位小鼠模型。其中包括免疫功能正常的小鼠同种异体移植模型和来自 MET 融合 IHG 患者的患者源性原位异种移植物 (PDOX)，该患者常规治疗和卡博替尼靶向治疗均失败。通过这些模型，我们分析了三种 MET 抑制剂（卡马替尼、克唑替尼和卡博替尼）单独或与放疗联合的疗效和药代动力学特性。在两种模型中，卡马替尼均表现出优于卡博替尼或克唑替尼的脑药代动力学特性以及更高的体外和体内疗效。 PDOX 模型概括了患者所经历的卡博替尼的不良疗效。相比之下，在两种互补的小鼠模型中，卡马替尼与放疗联合使用可延长生存期并诱导长期无进展生存期。卡马替尼治疗增加了辐射引起的 DNA 双链断裂并延迟了其修复。我们全面研究了 MET 抑制和放射治疗的组合作为 MET 驱动的 pHGG 的新型治疗选择。我们的开创性临床前数据包包括药代动力学特征、临床结果概述、多项补充体内研究的一致结果，以及对提高疗效的分子机制的见解。 综上所述，我们证明了卡马替尼和放射疗法的突破性功效，是未来临床试验中非常有前途的概念。