Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

Martyn A. Sharpe, Andrew D. Livingston, Taylor L. Gist, Pardip Ghosh, Junyan Han, David S. Baskin

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P+-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

Original languageEnglish (US)
Pages (from-to)1122-1132
Number of pages11
JournalEBioMedicine
Volume2
Issue number9
DOIs
StatePublished - Sep 1 2015

Keywords

  • Chemotherapy
  • Glioblastoma multiforme
  • MP-MUS
  • Monoamine oxidase B
  • Pro-drug
  • Xenograft

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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