治疗抵抗仍然是成功处理脑干高级儿童肿瘤Diffuse Intrinsic Pontine Glioma (DIPG)的临床管理的主要障碍。几乎所有患者中，现有的治疗都无法阻止病情恶化。迫切需要创新的组合疗法，能够穿越血脑屏障，实现长期控制肿瘤生长。我们确定了DIPG对放疗的抵抗机制，这是DIPG的标准治疗方法。基于这些发现，我们合理设计了一种能够穿越血脑屏障的小分子MTX-241F，它是选择性抑制剂EGFR和PI3激酶家族成员，包括DNA修复蛋白DNA-PK的。初步的研究表明，这种抑制剂在小鼠脑组织中可以达到微摩尔水平，并且MTX-241F在源于DIPG的神经球中展示出了有前景的单剂效力和放射敏感作用。其理化特性包括在大脑中的高暴露度，表明其优良的穿透性。由于放疗会导致通过同源重组（HR）和非同源DNA末端连接（NHEJ）修复的双链断裂，我们已经测试了MTX-241F与ATM抑制剂的联合应用，以分别实现HR和NHEJ的阻断，无论是否进行放疗。当HR阻断剂与MTX-241F和放疗联合使用时，观察到了合成致死作用，为在与DIPG相关的临床模型中探索这种联合应用提供了推动力。我们的数据为支持MTX-241F的DIPG治疗的前期开发提供了概念证明的证据。未来的研究将旨在迅速促进其临床应用，最终影响被诊断为这种毁灭性疾病的患者。

Therapeutic resistance remains a major obstacle to successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. Based on these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Since radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of ATM to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.