Background/Objectives: The advent of tyrosine kinase inhibitors (TKI), therapeutic antibodies and inducers of apoptosis has revolutionized cancer treatment, yet their application in pediatric tumors, particularly medulloblastoma, remains understudied. Understanding the expression of these targets in specific genetic subgroups could unveil potential repositioning opportunities for already approved drugs. Methods: We analyzed RNA-sequencing data from the R2 Genomics Analysis and Visualization Platform (N = 763 patients, multiple cohorts) and the TCGA database (six individual cohorts 828 patients) to assess the expression of 73 potential targets of TKIs and antibodies targeting immune checkpoint inhibitors (ICI) or membrane receptors and inducers of apoptosis. These treatments, FDA-approved or in phase II clinical trials for solid or hematologic cancers, and their targets were evaluated in both non-metastatic and metastatic patients when data was available. Additionally, we examined treatments tailored to mutated targets crucial for tumorigenesis or resistance to conventional therapies. Results: Overexpression of certain targets beyond predefined cutoff values in Kaplan–Meier analyses correlated with either prolonged or shortened overall survival. Targets associated with shorter survival suggested potentially relevant treatments, thereby highlighting the importance of defining specific treatments for distinct genetic subgroups. Notably, certain immune checkpoint inhibitors showed relevance for specific subgroups but detriment for others. As a positive control, our analysis confirmed the use of axitinib, an anti-angiogenic treatment, as demonstrated by our recent publication. Surprisingly, a treatment developed for hematological tumors, venetoclax, demonstrated potential efficacy in medulloblastoma. Conclusions: Medulloblastoma displays subtype-specific expressions of FDA-approved TKI, ICI and pro-apoptotic drug targets, impacting overall survival. Clinical trials investigating these approved treatments in medulloblastoma are therefore warranted.
背景/目的：酪氨酸激酶抑制剂（TKI）、治疗性抗体及凋亡诱导剂的出现已彻底改变了癌症治疗格局，然而它们在儿童肿瘤特别是髓母细胞瘤中的应用仍研究不足。解析这些靶点在特定遗传亚群中的表达模式，可能为已获批药物揭示潜在的重新定位机会。方法：我们通过R2基因组学分析与可视化平台（N=763例患者，多队列）及TCGA数据库（6个独立队列828例患者）的RNA测序数据，评估了73个TKI潜在靶点、靶向免疫检查点抑制剂（ICI）或膜受体的抗体靶点以及凋亡诱导剂靶点的表达情况。这些治疗手段（包括FDA批准或处于II期临床试验阶段，适用于实体瘤或血液肿瘤）及其对应靶点，在数据可及的情况下均于非转移性与转移性患者中进行评估。此外，我们还针对肿瘤发生或传统疗法耐药关键突变靶点，考察了相应的个体化治疗方案。结果：Kaplan-Meier分析显示，部分靶点的过表达（超过预设截断值）与患者总生存期的延长或缩短相关。与较短生存期相关的靶点提示了潜在相关治疗方案，从而凸显了针对不同遗传亚群制定特异性治疗策略的重要性。值得注意的是，某些免疫检查点抑制剂在特定亚群中显示相关性，但对其他亚群可能产生不利影响。作为阳性对照，我们近期发表的研究证实了抗血管生成药物阿昔替尼的适用性，本次分析亦验证了这一结论。令人意外的是，针对血液肿瘤开发的维奈托克在髓母细胞瘤中展现出潜在疗效。结论：髓母细胞瘤表现出具有亚型特异性的FDA批准TKI、ICI及促凋亡药物靶点表达特征，这些特征影响患者总生存期。因此，有必要开展临床试验，在髓母细胞瘤中进一步验证这些已获批疗法的疗效。
肿瘤(癌症)患者之家