Aix-Marseille University, AP-HM, Inserm, MMG, Neurosurgery department, La Timone Hospital, Marseille, France.
Aix-Marseille University, AP-HM, CNRS, INP, Inst Neurophysiopathol, CHU Timone, Service de Neurooncologie, Marseille, France.
Rev Neurol (Paris). 2023 Jun;179(5):449-463. doi: 10.1016/j.neurol.2023.03.006. Epub 2023 Mar 21.
Multi-recurrent high-grade meningiomas remain an unmet medical need in neuro-oncology when iterative surgeries and radiation therapy sessions fail to control tumor growth. Nevertheless, the last 10years have been marked by multiple advances in the comprehension of meningioma tumorigenesis via the discovery of new driver mutations, the identification of activated intracellular signaling pathways, and DNA methylation analyses, providing multiple potential therapeutic targets. Today, Anti-VEGF and mTOR inhibitors are the most used and probably the most active drugs in aggressive meningiomas. Peptide radioactive radiation therapy aims to target SSTR2A receptors, which are strongly expressed in meningiomas, but have an insufficient effect in most aggressive meningiomas, requiring the development of new techniques to increase the dose applied to the tumor. Based on the multiple potential intracellular targets, multiple targeted therapy clinical trials targeting Pi3K-Akt-mTOR and MAP kinase pathways as well as cell cycle and particularly, cyclin D4-6 are ongoing. Recently discovered driver mutations, SMO, Akt, and PI3KCA, offer new targets but are mostly observed in benign meningiomas, limiting their clinical relevance mainly to rare aggressive skull base meningiomas. Therefore, NF2 mutation remains the most frequent mutation and main challenging target in high-grade meningioma. Recently, inhibitors of focal adhesion kinase (FAK), which is involved in tumor cell adhesion, were tested in a phase 2 clinical trial with interesting but insufficient activity. The Hippo pathway was demonstrated to interact with NF2/Merlin and could be a promising target in NF2-mutated meningiomas with ongoing multiple preclinical studies and a phase 1 clinical trial. Recent advances in immune landscape comprehension led to the proposal of the use of immunotherapy in meningiomas. Except in rare cases of MSH2/6 mutation or high tumor mass burden, the activity of PD-1 inhibitors remains limited; however, its combination with various radiation therapy modalities is particularly promising. On the whole, therapeutic management of high-grade meningiomas is still challenging even with multiple promising therapeutic targets and innovations.
多复发高级别脑膜瘤在神经肿瘤学中仍然是一个未满足的医疗需求，当反复手术和放射治疗不能控制肿瘤生长时。尽管如此，过去 10 年，通过发现新的驱动突变、鉴定激活的细胞内信号通路和 DNA 甲基化分析，脑膜瘤肿瘤发生学的理解取得了多项进展，为多种潜在的治疗靶点提供了依据。如今，抗 VEGF 和 mTOR 抑制剂是侵袭性脑膜瘤中最常用和最有效的药物。肽放射性放射治疗旨在靶向 SSTR2A 受体，该受体在脑膜瘤中强烈表达，但在大多数侵袭性脑膜瘤中效果不足，需要开发新技术来增加应用于肿瘤的剂量。基于多种潜在的细胞内靶点，针对 Pi3K-Akt-mTOR 和 MAP 激酶途径以及细胞周期，特别是细胞周期蛋白 D4-6 的多种靶向治疗临床试验正在进行中。最近发现的驱动突变 SMO、Akt 和 PI3KCA 提供了新的靶点，但主要观察到良性脑膜瘤中，主要局限于罕见的侵袭性颅底脑膜瘤，因此其临床相关性有限。因此，NF2 突变仍然是高级别脑膜瘤中最常见的突变和主要挑战靶点。最近，参与肿瘤细胞黏附的黏着斑激酶（FAK）抑制剂在一项 II 期临床试验中进行了测试，结果显示出有趣但不充分的活性。Hippo 通路已被证明与 NF2/ Merlin 相互作用，在 NF2 突变脑膜瘤中可能是一个很有前途的靶点，目前正在进行多项临床前研究和一项 I 期临床试验。对免疫景观理解的最新进展导致了在脑膜瘤中使用免疫疗法的建议。除了在罕见的 MSH2/6 突变或高肿瘤负荷的情况下，PD-1 抑制剂的活性仍然有限；然而，它与各种放射治疗方式的联合应用具有特别的前景。总的来说，即使有多个有前途的治疗靶点和创新，高级别脑膜瘤的治疗管理仍然具有挑战性。
