Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, Germany.
Mol Cancer. 2024 Jun 7;23(1):123. doi: 10.1186/s12943-024-02027-6.
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.
小儿型弥漫性高级别神经胶质瘤（pHGG）是儿童中最常见的恶性脑肿瘤，可分为多个实体。激活 MET 受体酪氨酸激酶的融合基因通常发生在婴儿型大脑半球胶质瘤（IHG）中，但也发生在其他 pHGG 中，并与毁灭性的发病率和死亡率相关。
为了寻找新的治疗选择，我们建立并鉴定了两种具有不同 MET 融合的新型原位小鼠模型。这些模型包括免疫功能健全的鼠异体移植模型和来自一名 MET 融合 IHG 患者的患者来源的原位异种移植（PDOX），该患者对常规治疗和靶向治疗药物卡博替尼均无效。利用这些模型，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联合放疗的疗效和药代动力学特性。
卡马替尼在两种模型中的脑药代动力学特性优于卡博替尼或克唑替尼，体外和体内疗效也优于卡博替尼或克唑替尼。PDOX 模型重现了该患者卡博替尼疗效不佳的情况。相比之下，卡马替尼与放疗联合使用时，在两种互补的小鼠模型中延长了生存期并诱导了长期无进展生存期。卡马替尼治疗增加了辐射诱导的 DNA 双链断裂并延迟了其修复。
我们全面研究了 MET 抑制与放疗联合作为 MET 驱动的 pHGG 的一种新的治疗选择。我们的开创性临床前数据包括药代动力学特征、临床结果重现、多个互补体内研究的一致结果以及对提高疗效的分子机制的深入了解。综上所述，我们证明了卡马替尼和放疗作为未来临床试验极有前途的概念具有突破性的疗效。
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