Docetaxel targets aggressive methylation profiles and serves as a radiosensitizer in high-risk meningiomas.
Neuro Oncol
; 25(3): 508-519, 2023 03 14.
Article
en En
| MEDLINE
| ID: mdl-35976058
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.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Meníngeas
/
Meningioma
/
Antineoplásicos
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Idioma:
En
Revista:
Neuro Oncol
Asunto de la revista:
NEOPLASIAS
/
NEUROLOGIA
Año:
2023
Tipo del documento:
Article