Meningioma genomics: a therapeutic challenge for clinicians

Abstract

Meningiomas are amongst the most commonly encountered intracranial tumors. The majority of these tumors arise intracranially, and the remaining incidents occur along the spinal cord. Meningiomas tend to grow gradually, with many tumors arising in inaccessible locations. Such sporadic behavior poses a therapeutic challenge to clinicians, causing incomplete tumor resections that often lead to recurrence. Therefore, ongoing research seeks to find alternative systematic treatments for meningiomas, with gene-based therapeutics of high interest. Subsequently, genetic studies characterized frequent somatic mutations in NF2, TRAF7, KLF4, AKT1, SMO, and PIK3CA. These genes are communally exhibited in 80% of sporadic meningiomas. In addition, other genes such as the DUSP family, the NR4 family, CMKOR, and FOSL2, have been identified as key players in spinal meningiomas. In this perspective, we aim to investigate current genetic-based studies, with the ongoing research mainly focused on the above NF2, TRAF7, KLF4, AKT1, SMO, and PIK3CA genes and their involved pathways. In addition, this perspective can serve as a potential cornerstone for future genetic analyses of meningioma cases.

Bone Invasive Meningioma: Recent Advances and Therapeutic Perspectives

“…Most recently, technological developments have suggested that a higher rate of malignant meningiomas may be induced by increasing hypodiploidy, complex ablations, and even epigenetics (77)(78)(79)(80). Furthermore, certain characteristics have been correlated with histological subtypes, especially copy number alterations and mutations, suggesting a greater potential for gene therapy (58,80).…”

“…Most recently, technological developments have suggested that a higher rate of malignant meningiomas may be induced by increasing hypodiploidy, complex ablations, and even epigenetics (77)(78)(79)(80). Furthermore, certain characteristics have been correlated with histological subtypes, especially copy number alterations and mutations, suggesting a greater potential for gene therapy (58,80). Cytogenetics of lymphoplasmacyte-rich meningioma, a rare type of WHO grade 1 arising as an en plaque meningioma, is worth investigating, to develop therapeutic strategies for bone invasive meningioma.…”

“…However, their efficacy is limited. Thus far, there is no established evidence for their use, and more studies are required to unravel the mechanistic roles in bone-invasive meningiomas and across the entire meningioma spectrum (58,78,80,(153)(154)(155).…”

Potential Molecular Mechanisms of Recurrent and Progressive Meningiomas: A Review of the Latest Literature

“…FAK , which encodes a cytoplasmic protein tyrosine kinase that mediates cell growth, proliferation, and survival, is overexpressed in some meningiomas ( 31 ). Ribociclib, a cyclin-dependent kinase (CDK) inhibitor, was evaluated for its effect on other highly mutated genes (other than the common NF2 ), such as AKT1 and SMO (NCT02933736) ( Table 1 ) ( 38 ). Moreover, a national Alliance-sponsored cooperative group phase II clinical trial evaluated the efficacy of SMO, AKT1, and FAK inhibitors for recurrent or progressive meningiomas with targetable alterations in SMO, AKT1, and NF2, respectively (NCT02523014/A071401) ( 5 ).…”

“…A FAK inhibitor (GSK2256098) was identified to significantly improve the survival rates of patients with recurrent or progressive NF2-mutated meningiomas (NCT02933736) ( 108 ). Further, a phase II trial revealed another MEK1/2 inhibitor, selumetinib, to have an effect on NF2-related meningiomas (NCT03095248) ( 5 , 38 ). These advances on NF2-related meningiomas represent a major step forward in therapeutics.…”