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Abstract：
Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection, craniospinal irradiation, and multi-agent chemotherapy. However, despite this combination of multiple aggressive modalities, recurrence of the disease remains a substantial concern, and treatment resistance is a rising issue. The development of this resistance results from the interplay of a myriad of anatomical properties, cellular processes, molecular pathways, and genetic and epigenetic alterations. In fact, several efforts have been directed towards this domain and characterizing the major contributors to this resistance. Herein, this review highlights the different mechanisms that drive relapse and are implicated in the occurrence of treatment resistance and discusses them in the context of the latest molecular-based classification of medulloblastoma. These mechanisms include the impermeability of the blood-brain barrier to drugs, the overactivation of specific molecular pathways, the resistant and multipotent nature of cancer stem cells, intratumoral and intertumoral heterogeneity, and metabolic plasticity. Subsequently, we build on that to explore potential strategies and targeted agents that can abrogate these mechanisms, undermine the development of treatment resistance, and augment medulloblastoma\'s response to therapeutic modalities.
摘要：
髓母细胞瘤是儿科人群中最常见的恶性脑肿瘤。目前的护理标准包括手术切除，颅骨脊髓照射,和多药化疗。然而,尽管结合了多种侵略性方式，这种疾病的复发仍然是一个很大的问题，治疗抵抗是一个日益严重的问题。这种抗性的发展是由无数解剖学性质的相互作用引起的，细胞过程，分子途径，以及遗传和表观遗传改变。事实上,已经针对这一领域进行了一些努力，并描述了这种抵抗的主要贡献者。在这里，这篇综述重点介绍了导致复发的不同机制以及与治疗耐药性的发生有关的不同机制,并结合最新的髓母细胞瘤分子分类进行了讨论.这些机制包括血脑屏障对药物的不渗透性，特定分子途径的过度激活，癌症干细胞的抗性和多能性质，肿瘤内和肿瘤间异质性，和代谢可塑性。随后，我们在此基础上探索可以废除这些机制的潜在策略和有针对性的代理，破坏治疗抗性的发展，并增强髓母细胞瘤对治疗方式的反应。
