Docetaxel targets aggressive methylation profiles and serves as a radiosensitizer in high-risk meningiomas

Mark W. Youngblood, Anh N. Tran, Wenxia Wang, Shejuan An, Denise Scholtens, Lyndsee Zhang, Kaitlyn O'Shea, Jenny L. Pokorny, Stephen T. Magill, Sean Sachdev, Rimas V. Lukas, Atique Ahmed, Dusten Unruh, Jordain Walshon, Kathleen McCortney, Yufen Wang, Aneta Baran, Felix Sahm, Kenneth Aldape, James P. ChandlerC. David James, Amy B. Heimberger, Craig Horbinski

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

BACKGROUND: Meningioma is the most common primary intracranial tumor in adults. A subset of these tumors recur and invade the brain, even after surgery and radiation, resulting in significant disability. There is currently no standard-of-care chemotherapy for meningiomas. As genomic DNA methylation profiling can prognostically stratify these lesions, we sought to determine whether any existing chemotherapies might be effective against meningiomas with high-risk methylation profiles. METHODS: A previously published dataset of meningioma methylation profiles was used to screen for clinically significant CpG methylation events and associated cellular pathways. Based on these results, patient-derived meningioma cell lines were used to test candidate drugs in vitro and in vivo, including efficacy in conjunction with radiotherapy. RESULTS: We identified 981 genes for which methylation of mapped CpG sites was related to progression-free survival in meningiomas. Associated molecular pathways were cross-referenced with FDA-approved cancer drugs, which nominated Docetaxel as a promising candidate for further preclinical analyses. Docetaxel arrested growth in 17 meningioma cell sources, representing all tumor grades, with a clinically favorable IC50 values ranging from 0.3 nM to 10.7 mM. The inhibitory effects of this medication scaled with tumor doubling time, with maximal benefit in fast-growing lesions. The combination of Docetaxel and radiation therapy increased markers of apoptosis and double-stranded DNA breaks, and extended the survival of mice engrafted with meningioma cells relative to either modality alone. CONCLUSIONS: Global patterns of DNA methylation may be informative for the selection of chemotherapies against meningiomas, and existing drugs may enhance radiation sensitivity in high-risk cases.

Original languageEnglish (US)
Pages (from-to)508-519
Number of pages12
JournalNeuro-oncology
Volume25
Issue number3
DOIs
StatePublished - Mar 14 2023

Keywords

  • DNA methylation
  • Docetaxel
  • chemotherapy
  • meningioma
  • radiotherapy

ASJC Scopus subject areas

  • Clinical Neurology
  • Oncology
  • Cancer Research

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