Diffuse midline gliomas (DMG) are rapidly fatal tumors of the midbrain in children, characterized by a diffuse growing pattern and high levels of intrinsic resistance to therapy. The location of these tumors, residing behind the blood-brain barrier (BBB), and the limited knowledge about the biology of these tumors, has hindered the development of effective treatment strategies. However, the introduction of diagnostic biopsies and the implementation of autopsy protocols in several large centers world-wide has allowed for a detailed characterization of these rare tumors. This has resulted in the identification of novel therapeutic targets, as well as major advances in understanding the biology of DMG in relation to therapy resistance. We here provide an overview of the cellular pathways and tumor-specific aberrations that have been targeted in preclinical DMG research, and discuss the advantages and limitations of these therapeutic strategies in relation to therapy resistance and BBB-penetration. Therewith, we aim to provide researchers with a framework for successful preclinical therapy development.

弥漫性中线神经胶质瘤（DMG）是儿童中脑的快速致命性肿瘤，其特征在于弥漫性生长模式和对治疗的固有抗性高水平。这些肿瘤位于血脑屏障（BBB）后的位置，以及对这些肿瘤生物学的有限了解，阻碍了有效治疗策略的发展。然而，在世界范围内的几个大型中心中，诊断性活检的引入和尸检协议的实施已经允许对这些罕见肿瘤进行详细的表征。这导致了新的治疗靶标的鉴定，以及在理解DMG与治疗耐药性相关的生物学方面的重大进展。我们在这里提供了临床前DMG研究中针对的细胞途径和肿瘤特异性畸变的概述，并讨论了这些治疗策略相对于治疗耐药性和BBB渗透的优势和局限性。因此，我们旨在为研究人员提供成功的临床前治疗开发框架。