Format

Send to

Choose Destination
J Neurooncol. 2018 Sep;139(3):713-720. doi: 10.1007/s11060-018-2917-2. Epub 2018 Jun 5.

Rethinking medulloblastoma from a targeted therapeutics perspective.

Author information

1
Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
2
Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
3
Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
4
Department of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
5
Division of Neurosurgical Oncology, Barrow Neurological Institute, Phoenix, AZ, USA.
6
Caris Life Sciences, Phoenix, AZ, USA.
7
Department of Neurological Surgery and Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
8
Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute and John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
9
Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. aheimber@mdanderson.org.
10
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Unit 442, Houston, TX, 77030, USA. aheimber@mdanderson.org.

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.

KEYWORDS:

Medulloblastoma; Molecular profiling; Targeted therapy

PMID:
29869738
PMCID:
PMC6132970
DOI:
10.1007/s11060-018-2917-2
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center