Table 2.

Details of some common signaling pathway inhibitors used in target therapy for the treatment of meningioma

Drug name	Drug composition/molecular formula administration			Mechanism of action	Type of study		References
EGFR antagonists
Gefitinib (Iressa)		It is an anilinoquinazoline with anticancer activity, orally administered	It competes with ATP for binding to the EGFR’s tyrosine kinase domain, inhibiting receptor autophosphorylation and signal transmission; it is also in charge of stopping the cell cycle and preventing angiogenesis			The study showed its involvement in the treatment of meningioma as an EGFR antagonist; phase: no survival benefit shown		[73]
Erlotin ib (Tarceva)		C22H23N3O4 is a quinazoline derivative with anticancer activity, orally given	Similar to gefitinib, it competes with ATP binding to the tyrosine kinase domain of EGFR, thereby inhibiting autophosphorylation of EGFR and blocking signal transduction			Its use in meningioma treatment is underway; phase II: no survival benefit shown		[73]
Lapatinib		C43H42ClFN4O10S3 is a small molecule and a dual EGFR/ErbB2 inhibitor, as shown by preclinical and clinical data, orally given	EGFR antagonist			Effect of lapatinib on meningioma growth in adults with neurofibromatosis type 2 revealed anticancer activity against schwannomas; it is also hypothesized to have growth-inhibitory effects on meningiomas (Fig. 1)		[74]
Monoclonal antibodies, humanized monoclonal antibodies of EGFR
Cetuximab		Fv region of a murine anti-EGFR antibody with human IgG1 heavy and kappa light chain constant regions	By binding to EGFR on a cancer cell, cetuximab blocks EGF from binding (activation); this stops the cell from continuing the pathway that promotes cell division and growth, effectively stopping cancer by stopping the cancerous cells from growing and multiplying			Assessment of epidermal growth factor receptor (EGFR) expression in human meningioma		[75]
Panitumumab		ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor	Panitumumab works by binding to the extracellular domain of the EGFR preventing its activation; this results in halting the cascade of intracellular signals dependent on this receptor			Is there effective systemic therapy for recurrent surgery- and radiation-refractory meningioma?		[76]
Matuzumab (EMD72000)		A fully humanized ErbB-1-specific monoclonal antibody	Matuzumab binds to the epidermal growth factor receptor (EGFR) on the outer membrane of normal and tumor cells; the matuzumab epitope has been mapped to domain III of the extracellular domain of the EGFR			Innovative therapeutic strategies in the treatment of meningioma		[77]
mAb 806		mAb 806 is a second-generation antibody	Depatuxizumab selectively targets a unique epitope on the epidermal growth factor receptor (EGFR), which is only expressed on cancer cells (and not on normal cells)			Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-κB and initiates tumor vascular normalization		[78]
Nimotuzumab		Nimotuzumab (also known by the lab code h-R3) is a humanized IgG1 isotype monoclonal antibody	Nimotuzumab binds with optimal affinity and high specificity to the extracellular region of EGFR (epidermal growth factor receptor). This results in a blockade of ligand binding and receptor activation; epidermal growth factor receptor (EGFR) is a key target in the development of cancer therapeutics			Nimotuzumab is a promising therapeutic monoclonal for the treatment of tumors of epithelial origin		[79]
PDGFR antagonists
Imatinib (Gleevec)		C30H35N7O4S is a 2-phenyl amino pyrimidine derivative, orally given	Imatinib mesylate (Gleevec) is an inhibitor of PDGFR-a and b, Bcr –Abl, c-Fms, and c-Kit tyrosine kinases, which are responsible for abnormal cell growth through its constitutive expression; it has the power to inhibit PDGFR-a or b, which makes it a superior meningioma therapeutic alternative			The North American Brain Tumor Consortium (NABTC) evaluated the efficacy of imatinib in meningioma patients PDGFR antagonist; phase II: some stabilization of disease		[80]
Nilotinib		C28H22F3N7O, orally given	Second-generation PDGFR inhibitor			Nilotinib alone or in combination with selumetinib is a drug candidate for neurofibromatosis type 2; no studies		[81]
Dasatinib		C22H26ClN7O2S, orally given	Dasatinib inhibits the growth-promoting actions of SRC-family protein tyrosine kinases by binding to them; PDGFR antagonist			Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma; dasatinib is a multikinase inhibitor targeting SFKs, several EPH receptors, and c-Kit23 dasatinib and AZD2014 combination therapy was performed on NF2-deficient meningioma cells; in vivo and in vitro, this combination therapy efficiently inhibited the development of NF2-deficient meningioma cells; dasatinib and AZD2014 combined therapy was more effective than either monotherapy		[82]
Tandutinib		C31H42N6O4 is a piperazinyl quinazoline, a potent anticancer agent,that specifically acts on the angiogenic pathways, orally given	This is a tyrosine kinase inhibitor that targets PDGFRb, C-Kit, and Fms-like tyrosine kinase 3 (FLT3), thereby inhibiting cellular proliferation and inducing apoptosis (Fig. 1); PDGFR B antagonist			Vascular endothelial growth factor signals through platelet-derived growth factor receptor β in meningiomas in vitro		[61]
VEGFR antagonists
Bevacizumab (Avastin)		Bevacizumab is a full-length IgG1κ isotype antibody composed of two identical light chains (214 amino-acid residues) and two heavy chains (453 residues), intravenous infusion	Bevacizumab was engineered as a humanized monoclonal antibody to VEGF receptors that inhibits the binding and signaling cascade required for vascularization, as it leads to diminished tumor blood supply			Recently, numerous studies on anti-angiogenesis have been conducted on meningioma humanized monoclonal antibodies of EGFR; SSCTs: mixed results		[83]
Cediranib (recentin)		C25H27FN4O3, also called AZD2171, is a potent anticancer agent, orally given	It is a small-molecule tumor kinase inhibitor of VEGFRs that also targets c-KIT and PDGFR-a			The effect of cediranib has been studied in various types of cancers, and 81 clinical trials have been conducted; it is currently being analyzed in juvenile recurrent CNS malignancies in phase I clinical trials (Fig. 1);VEGFR antagonist; no studies		[84]
Combination antagonists
Sorafenib (Nexavar)		C21H16ClF3N4O3 is a multi-tyrosine kinase synthetic inhibitor, orally administered	It is a potent anticancer agent with antiangiogenetic and cytostatic effects; it was the first approved angiogenetic multikinase inhibitor; this compound targets RAF kinase of the RAF/MEK/ERK signaling pathway and inhibits the VEGFR-2/PDGFR beta signaling cascade, thereby preventing tumor angiogenesis			Receptor tyrosine kinase inhibition by regorafenib/sorafenib inhibits the growth and invasion of meningioma cells		[85]
Sunitinib (Sutent)		C22H27FN4O2 is a pyrrole and a monocarboxylic acid amide with potent anticancer activity, orally given	Inhibitor of VEGFR, PDGFR, and KIT tyrosine kinase; sunitinib blocks the tyrosine kinase activity of VEGFR and PDGFR; it inhibits angiogenesis and cell proliferation			Sunitinib is widely used in cancer treatment; association between meningioma and sunitinib was seen in studies; dual VGFER and PDGFR antagonist; phase II: some stabilization of disease		[86]
Vatalanib (PTK-787)		C20H15ClN4 is an anilinophthalazine with potential anticancer activity, orally administered	Vatalanib, also called PTK787, is an inhibitor of VEGFR-1 (Flt-1), VEGFR-2 (KDR), and VEGFR3 (Flt4), by binding to the protein kinase domain of VEGFRs; dual VGFER and PDGFR antagonist; vatalanib induces a dose-dependent inhibition of VEGF-induced angiogenesis, as well as tumor-derived angiogenesis; it also binds to the tyrosine kinase domain of other receptors such as PDGFR, C-Fms, and c-Kit			Preclinical studies showed that, when given orally to orthotopic models, some stabilization of disease occurred		[69]
Farnesyl transferase inhibitors
Tipifarnib (Zrnestra)		C27H22Cl2N4O is a nonpeptidomimetic quinolinone and is a potent anticancer agent, orally administered	Farnesyl protein transferase is an enzyme that causes protein farnesylation and is involved in signal transduction; tipifarnib binds to and inhibits this enzyme, thereby inhibiting protein processing; it stops Ras oncogenes from being activated, resulting in the induction of apoptosis, as well as the prevention of cell proliferation and angiogenesis			Research on the use of tipifarnib against meningioma is underway		[69]
mTOR inhibitors
Temsirolimus (Torisel)		C56H87NO16 is an ester analog of rapamycin and a kinase inhibitor, intravenous infusion	Temsirolimus inhibits mTOR after attaching to it, leading to the downregulation of mRNAs required for cell-cycle progression; the cell cycle is halted in the G1 phase; mTOR is a serine/threonine kinase that is involved in the PI3K/AKT signaling cascade; mTOR has been discovered to be elevated in certain malignancies; as it is like a protein kinase inhibitor, inhibition of mTOR activation is a kind of therapy for treating various types of cancers			Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04–02		[87]
Everolimus (Afinitor)		C53H83NO14 is derived from the macrocyclic lactone sirolimus in nature; it is an immunosuppressant, antiangiogenic, and anti-cell proliferative agent, orally given	Everolimus is an inhibitor that forms an immunosuppressive complex with the immunophilin FK binding protein-12 (FKBP-12), which then binds to and inhibits mTOR (mammalian target of Rapamycin); because mTOR is a regulatory kinase, it causes the production of mRNA that codes for cell-cycle proteins and hinders the glycolysis process, thus inhibiting tumor growth; as already explained, mTOR is upregulated in cancer and, hence, inhibition of mTOR activation may help in cancer treatment			Antitumor effect of everolimus in the case of grade III meningioma was reported; mTOR inhibitor; phase I		[88]
Vistusertib		C25H30N6O3 is an antineoplastic agent and is administered orally	It is an inhibitor of the mammalian target of rapamycin (mTOR); it inhibits mTORC1 and mTORC2, leading to tumor cell death and a reduction in tumor cell growth; it is a serine/threonine kinase that is involved in the PI3K/Akt/mTOR signaling cascade; its suppression is the cornerstone of anticancer therapy because it is elevated in a variety of malignancies			Vistusertib (AZD2014) is under investigation for the treatment of advanced gastric adenocarcinoma; mTOR C1 and C2 inhibitor; phase II		[69]
Akt inhibitors
AZD5363/capivasertib		It is a novel pyrrolopyrimidine derivative with a potency of 10 nM or less in inhibiting the AKT isoform, orally administered	Capivarsertib inhibited the phosphorylation of AKT (Iat, Ser, and Thr) in BT474c cells in three cell lines; in vivo investigations revealed that, when given orally to nude mice, it reduced the phosphorylation of PRAS40, GSK3, and S6 in BT474c xenografts in a dose- and time-dependent manner; it inhibited the growth of xenografts in a dose-dependent manner in a variety of malignancies (Fig. 1)			Durable control of metastatic AKT1-mutant WHO grade 1 meningothelial meningioma was shown using the Akt inhibitor AZD5363		[89]
Afuresurtib		C18H17Cl2FN4OS is an orally administered drug	Afuresurtib is an inhibitor of Akt, a protein kinase inhibitor, and thus, a potent anticancer agent; afuresurtib inhibits Akt, which is increased in several types of cancer and is implicated in the PI3K/Akt signaling pathway, resulting in tumor growth inhibition and induction of apoptosis			Emerging medical treatments for meningioma in the molecular era		[90]
PI3K inhibitor
Alpelisib		C19H22F3N5O2S is a well-tolerated drug given orally	Phosphoinositide 3-kinase α (PI3Kα)-specific inhibitor; cell development and survival may be inhibited as a result			Phase I trial of alpelisib in combination with concurrent cisplatin-based chemoradiotherapy in patients with locoregionally advanced squamous cell carcinoma of the head and neck showed that alpelisib in combination with trametinib can be used to treat aggressive and recurrent meningioma		[91]
CDK4/6 inhibitors
Palbociclib		C24H29N7O2 is an orally available cyclin-dependent kinase (CDK) inhibitor with potential anticancer properties, orally administered	CDK4 and 6 are serine/threonine kinases that regulate cell-cycle progression and are overexpressed in several malignancies; palbociclib inhibits cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), which leads to cell-cycle arrest by inhibiting retinoblastoma (Rb) protein phosphorylation during the early G1 phase of the cell cycle; DNA replication is inhibited, and tumor cell proliferation is reduced			Palbociclib had effects in combination with radiation in preclinical models of aggressive meningioma; CDK4/6 inhibitor		[92]
Ribociclib		C23H30N8O is orally given	CDK4/6 inhibitor			Ribociclib (LEE011) in preoperative glioma and meningioma patients; phase I		[69]
Abemaciclib		C27H32F2N8 is orally given	CDK4/6 inhibitor			Meningioma is not always a benign tumor: a review of advances in the treatment of meningiomas		[93]
MEK1/2 inhibitors
Trametinib		C26H23FIN5O4 is an inhibitor of MAP2K/ERK kinase (MEK) 1 and 2 and a potent anticancer agent, orally given	Trametinib inhibits growth factor-mediated cell signaling and cellular proliferation in a variety of malignancies by targeting MEK 1 and 2, which are two types of MEK; MEK 1 and 2 are serine/threonine and tyrosine kinases with dual specificity that are commonly overexpressed in cancer; it affects cell proliferation by activating the RAS/RAF/MEK/ERK signaling pathway			Trametinib is used in combination with dabrafenib for the treatment of advanced malignant melanoma		[94]
Selumetinib		C17H15BrClFN4O3 is a small molecule that has potential anticancer activity, used to treat symptomatic, refractory fibroma in neurofibromatosis type 1, orally given	The RAS/RAF/MEK/ERK pathway regulates a variety of cellular activities, including proliferation; this pathway is abnormally regulated in cancer, and MEK1 and 2, which are dual-specificity kinases, are overexpressed; selumetinib inhibits mitogen-activated protein kinases (MEK or MAPK/ERK kinases) 1 and 2, resulting in cellular proliferation suppression in a variety of malignancies			Trial of selumetinib in patients with neurofibromatosis type II-related tumors (SEL-TH-1601)		[69]
ERK inhibitor
Regorafenib		C21H15ClF4N4O3 is orally given	ERK inhibitor			Receptor tyrosine kinase inhibition by regorafenib/sorafenib inhibits the growth and invasion of meningioma cells		[85]
Hedgehog pathway inhibitors
Vismodegib		C19H14Cl2N2O3S, also called aDC-0449, is a small molecule and a potent anticancer agent. SMO inhibitor, orally given	Vismodegib is a Hedgehog antagonist that works by inhibiting Hedgehog signaling; it suppresses Hedgehog signaling by blocking the activity of the Hedgehog ligand cell surface receptors PTCH and/or SMO; the Hedgehog signaling system is so important for tissue growth and repair that its improper and constitutive activation leads to uncontrolled cellular proliferation			Vismodegib, FAK inhibitor GSK2256098, capivasertib, and abemaciclib in treating patients with progressive meningiomas; phase II		[69]
Sonidegib		C26H26F3N3O3 is a small molecule that is administered orally for cellular growth, differentiation, and repair	It is an antagonist of smoothened (SMO), which shows potential antineoplastic activity; in cancer cells where the hedgehog pathway is abnormally activated, sonidegib inhibits the Hh signaling cascade by binding to the hedgehog (Hh) ligand cell surface receptor SMO; SMO inhibitor			Selective vulnerability of the primitive meningeal layer to prenatal SMO activation for skull base meningothelial meningioma formation; the Hh signaling pathway is responsible for this abnormal activation of the hedgehog path and way may be associated with a mutation in SMO		[95]
FAK inhibitors
GSK2256098		C20H23ClN6O2	FAK inhibitor			Vismodegib, FAK inhibitor GSK2256098, capivasertib, and abemaciclib in treating patients with progressive meningiomas; phase II		[69]