Rethinking medulloblastoma from a targeted therapeutics perspective

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)713-720
Number of pages8
JournalJournal of neuro-oncology
Volume139
Issue number3
DOIs
StatePublished - Sep 1 2018

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Medulloblastoma
Neoplasms
Therapeutics
Gene Amplification
Central Nervous System Neoplasms
Thymidylate Synthase
Mutation
Tumor Burden
Fluorescence In Situ Hybridization
In Situ Hybridization
Biomarkers
Immunohistochemistry
Clinical Trials
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Hashimoto, Y., Penas-Prado, M., Zhou, S., Wei, J., Khatua, S., Hodges, T. R., ... Heimberger, A. (2018). Rethinking medulloblastoma from a targeted therapeutics perspective. Journal of neuro-oncology, 139(3), 713-720. https://doi.org/10.1007/s11060-018-2917-2
Hashimoto, Yuuri ; Penas-Prado, Marta ; Zhou, Shouhao ; Wei, Jun ; Khatua, Soumen ; Hodges, Tiffany R. ; Sanai, Nader ; Xiu, Joanne ; Gatalica, Zoran ; Kim, Lyndon ; Kesari, Santosh ; Rao, Ganesh ; Spetzler, David ; Heimberger, Amy. / Rethinking medulloblastoma from a targeted therapeutics perspective. In: Journal of neuro-oncology. 2018 ; Vol. 139, No. 3. pp. 713-720.
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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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Hashimoto, Y, Penas-Prado, M, Zhou, S, Wei, J, Khatua, S, Hodges, TR, Sanai, N, Xiu, J, Gatalica, Z, Kim, L, Kesari, S, Rao, G, Spetzler, D & Heimberger, A 2018, 'Rethinking medulloblastoma from a targeted therapeutics perspective', Journal of neuro-oncology, vol. 139, no. 3, pp. 713-720. https://doi.org/10.1007/s11060-018-2917-2

Rethinking medulloblastoma from a targeted therapeutics perspective. / Hashimoto, Yuuri; Penas-Prado, Marta; Zhou, Shouhao; Wei, Jun; Khatua, Soumen; Hodges, Tiffany R.; Sanai, Nader; Xiu, Joanne; Gatalica, Zoran; Kim, Lyndon; Kesari, Santosh; Rao, Ganesh; Spetzler, David; Heimberger, Amy.

In: Journal of neuro-oncology, Vol. 139, No. 3, 01.09.2018, p. 713-720.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rethinking medulloblastoma from a targeted therapeutics perspective

AU - Hashimoto, Yuuri

AU - Penas-Prado, Marta

AU - Zhou, Shouhao

AU - Wei, Jun

AU - Khatua, Soumen

AU - Hodges, Tiffany R.

AU - Sanai, Nader

AU - Xiu, Joanne

AU - Gatalica, Zoran

AU - Kim, Lyndon

AU - Kesari, Santosh

AU - Rao, Ganesh

AU - Spetzler, David

AU - Heimberger, Amy

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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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