A Critical Appraisal of the Genotypic Features, Phenotypic Drivers and Therapeutic vulnerabilities in Recurrent Meningiomas

Meningiomas are the most common primary intracranial tumours of the Central Nervous system, responsiblefor roughly a third of all CNS neoplasms, and the most common neuro-oncological diagnosis in neurosurgicalpractice. Meningiomas have an annual incidence rate of 6 per 100,000 people in the United States, with thehighest incidence occurring after the 5th decade of life. Despite substantial advances in the last few decades inour understanding of meningioma biology and neurosurgical oncology, high-grade malignant anaplastic andatypical meningiomas remain incurable with no current disease-modifying therapeutic interventions. This isprimarily due to the highly unknown and heterogeneous nature of meningiomas which carry unpredictablepatterns of mutations, amplification, angiogenesis, proliferation and aberrant signalling pathways across allmalignant and recurrently diagnosed patients. Despite the sporadic pathogenesis of meningiomas, there havebeen promising molecular profiling ventures in characterising the genotypic features, phenotypic drivers andtherapeutic vulnerabilities present in malignant meningiomas over the last decade. Most of these ventureshave relied on emergent integration of proteomics, transcriptomic, whole-exome and single-cell sequencingstrategies to develop patient-stratified therapeutic strategies and prediction models of malignancy andrecurring meningiomas. The current paper outlines the fundamental pathophysiology, tumorgenicity,histological classification schemes, clinical presentations and treatment strategies of high-grade malignantmeningiomas. Lastly, the present paper aims to elucidate the biological drivers and emergent therapeuticvulnerabilities of high-grade meningiomas, particularly on the promising therapeutic role of cytostatic cellcycle inhibitor drugs in suppressing meningeal tumour cell growth and proliferation.