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Journal of Neuro-Oncology

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01-11-2018 | Laboratory Investigation

Bevacizumab, irinotecan, temozolomide, tyrosine kinase inhibition, and MEK inhibition are effective against pleomorphic xanthoastrocytoma regardless of V600E status

Authors: Eric M. Thompson, Daniel Landi, David Ashley, Stephen T. Keir, Darell Bigner

Published in: Journal of Neuro-Oncology | Issue 2/2018

Abstract

Introduction

Pleomorphic xanthoastrocytoma (PXA) is a rare Grade II and III glioma. Surgical resection is the mainstay of treatment, however, adjuvant therapy is sometimes necessary. Given the rarity of PXA, chemotherapeutic efficacy data is limited. The importance of the BRAF V600E mutation in the context of MAP kinase pathway inhibition is unknown. The purpose of this study was to perform an in vivo screen of a variety to agents to determine efficacy against both V600E mutant and non-mutant PXA.

Methods

The efficacy of bevacizumab, temozolomide, lomustine (CCNU), irinotecan (CPT 11), a tyrosine kinase inhibitor (sorafenib), a selective MEK1/2 inhibitor (cobimetinib), and a BRAF inhibitor (vemurafenib) were assessed in two subcutaneous xenografts: D645 PXA (V600E-mutant) and D2363 PXA (V600E-non-mutant) (n = 5–10 mice). Select agents were also assessed in an intracranial model of D2363 PXA (n = 6–9). Subcutaneous tumor growth and survival were the endpoints.

Results

Temozolomide, bevacizumab, CPT 11, and sorafenib significantly inhibited subcutaneous tumor growth in both V600E-mutant and V600E-non-mutant models (P < 0.05). MEK inhibition (cobimetinib) but not BRAF inhibition (vemurafenib) also inhibited tumor growth regardless of V600E mutation (P < 0.05). Temozolomide, CPT 11, and bevacizumab also prolonged survival in a V600E-non-mutant intracranial model (median overall survival (OS) 68.5, 62.5, and 42.5 days, respectively) in contrast to controls (31.5 days, P < 0.001).

Conclusions

These findings suggest that when adjuvant treatment is clinically indicated for PXA, temozolomide, CPT 11, or bevacizumab may be considered. Additionally, a trial of a MEK inhibitor or tyrosine kinase inhibitor could be considered for PXA regardless of V600E mutation status.

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Title: Bevacizumab, irinotecan, temozolomide, tyrosine kinase inhibition, and MEK inhibition are effective against pleomorphic xanthoastrocytoma regardless of V600E status
Authors: Eric M. Thompson
Daniel Landi
David Ashley
Stephen T. Keir
Darell Bigner
Publication date: 01-11-2018
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 2/2018
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-018-2975-5

Keynote webinar | Spotlight on medication adherence

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Bevacizumab, irinotecan, temozolomide, tyrosine kinase inhibition, and MEK inhibition are effective against pleomorphic xanthoastrocytoma regardless of V600E status

Abstract

Introduction

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

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