Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
J Neurooncol. 2018 Sep;139(3):713-720. doi: 10.1007/s11060-018-2917-2. Epub 2018 Jun 5.
Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. Analysis of therapeutic targets can provide opportunities for the selection of agents.
Using multiplatform analysis, 36 medulloblastomas were extensively profiled from 2009 to 2015. Immunohistochemistry, next generation sequencing, chromogenic in situ hybridization, and fluorescence in situ hybridization were used to identify overexpressed proteins, immune checkpoint expression, mutations, tumor mutational load, and gene amplifications.
High expression of MRP1 (89%, 8/9 tumors), TUBB3 (86%, 18/21 tumors), PTEN (85%, 28/33 tumors), TOP2A (84%, 26/31 tumors), thymidylate synthase (TS; 80%, 24/30 tumors), RRM1 (71%, 15/21 tumors), and TOP1 (63%, 19/30 tumors) were found in medulloblastoma. TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation between TOP2A and TOP1 expression (p = 0.0472). PD-1 + T cell tumor infiltration was rare, PD-L1 tumor expression was uncommon, and TML was low, indicating that immune checkpoint inhibitors as a monotherapy should not necessarily be prioritized for therapeutic consideration based on biomarker expression. Gene amplifications such as those of Her2 or EGFR were not found. Several unique mutations were identified, but their rarity indicates large-scale screening efforts would be necessary to identify sufficient patients for clinical trial inclusion.
Therapeutics are available for several of the frequently expressed targets, providing a justification for their consideration in the setting of medulloblastoma.
成神经管细胞瘤是一种侵袭性但可治愈的中枢神经系统肿瘤，仍然是治疗的挑战。治疗靶点的分析可为药物选择提供机会。
使用多平台分析，从 2009 年至 2015 年对 36 例成神经管细胞瘤进行了广泛的分析。免疫组织化学、下一代测序、显色原位杂交和荧光原位杂交用于鉴定过表达蛋白、免疫检查点表达、突变、肿瘤突变负荷和基因扩增。
在成神经管细胞瘤中发现 MRP1（89%，9/9 例肿瘤）、TUBB3（86%，18/21 例肿瘤）、PTEN（85%，28/33 例肿瘤）、TOP2A（84%，26/31 例肿瘤）、胸苷酸合成酶（TS；80%，24/30 例肿瘤）、RRM1（71%，15/21 例肿瘤）和 TOP1（63%，19/30 例肿瘤）表达较高。TOP1 在转移性肿瘤（90%，9/10 例）中的富集程度高于后颅窝病例（50%，10/20 例）（p=0.0485，Fisher 确切检验），并且 TOP2A 和 TOP1 表达之间存在正相关（p=0.0472）。PD-1+T 细胞肿瘤浸润罕见，PD-L1 肿瘤表达罕见，TML 低，这表明基于生物标志物表达，免疫检查点抑制剂作为单一疗法不一定应优先考虑治疗。未发现 Her2 或 EGFR 等基因扩增。鉴定出了一些独特的突变，但由于其罕见性，需要进行大规模筛选，才能为临床试验纳入足够的患者。
针对几种常见表达的靶点有治疗方法，这为在成神经管细胞瘤中考虑这些靶点提供了依据。
