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.
髓母细胞瘤是儿童中最常见的恶性脑肿瘤。目前的标准治疗方案包括手术切除、颅脊髓放疗以及多药联合化疗。然而，尽管采用了多种激进治疗手段的组合，疾病复发仍是重大隐患，而治疗耐药性问题也日益凸显。这种耐药性的产生源于多种解剖学特性、细胞过程、分子通路以及遗传和表观遗传改变的相互作用。事实上，已有诸多研究聚焦于该领域，致力于阐明导致耐药性的主要因素。本文综述了驱动肿瘤复发及参与治疗耐药性发生的不同机制，并结合髓母细胞瘤最新的分子分型进行探讨。这些机制包括血脑屏障对药物的不通透性、特定分子通路的过度激活、肿瘤干细胞的多能性与耐药性、肿瘤内及肿瘤间的异质性以及代谢可塑性。在此基础上，我们进一步探讨了可能阻断这些机制、抑制治疗耐药性发展并增强髓母细胞瘤对治疗手段反应性的潜在策略与靶向药物。
Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies
肿瘤(癌症)患者之家