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05.06.2018 | Clinical Study Open Access

Rethinking medulloblastoma from a targeted therapeutics perspective

Zeitschrift:
Journal of Neuro-Oncology
Autoren:
Yuuri Hashimoto, Marta Penas-Prado, Shouhao Zhou, Jun Wei, Soumen Khatua, Tiffany R. Hodges, Nader Sanai, Joanne Xiu, Zoran Gatalica, Lyndon Kim, Santosh Kesari, Ganesh Rao, David Spetzler, Amy Heimberger

Abstract

Introduction

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.

Methods

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.

Results

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.

Conclusions

Therapeutics are available for several of the frequently expressed targets, providing a justification for their consideration in the setting of medulloblastoma.

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Zusatzmaterial
Supplementary material 1 (DOCX 12 KB)
11060_2018_2917_MOESM1_ESM.docx
Supplementary material 2 (DOCX 18 KB)
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Supplementary material 3 (DOCX 15 KB)
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Supplementary Figure 1: mRNA expression levels in medulloblastoma patients (n=47) from TCGA.
11060_2018_2917_MOESM4_ESM.pptx
Literatur
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