**7. Platelet-Derived Growth Factor Receptor (PDGFR) inhibitors**

PDGFR is another RTK whose expression is critical during development, as well as in the growth and differentiation of certain cell lineages. Its role in multiple chronic diseases have been studied, and it is considered a possible target in conditions like cancer, fibrosis, neurological disorders and atherosclerosis. The PDGF/ PDGFR axis promotes cell proliferation, survival and migration primarily in cells of mesenchymal origin [106]. The ligands for PDGFR are four different polypeptide chains (PDGF-A, PDGF-B, PDGF-C and PDGF-D) which can be organized in an array of dimers that behave as functional growth factors (PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC and PDGF-DD [107]. These ligands have two different receptors, PDGFRα and PDGFRβ. The different ligands bind to the receptors with a differential specificity. PDGF-A, -B and -C will bind strongly to PDGFRα while the others will bind to PDGFRβ [106].

It has been demonstrated that MN expresses different forms of PDGF ligands, namely PDGF-AA and PDGF-BB, and expresses considerable levels of PDGFRβ. It has been shown that the PDGF/PDGFR axis might play a key role in the tumorigenesis of MN. Black et al. proved that PDGFRβ in MN cells derived from patients are susceptible to the stimulation with PDGF-BB ligands, with a shown increased in the activation of MAPK [21] and c-fos, a critical part of the master regulator AP-1, and a recognized proto-oncogene [108, 109]. Unlike EGFR expression, PDGFR levels appear to be higher in atypical and anaplastic MN than in grade I MN. In those MN that express PDGFR and the aforementioned PDGF ligands, there is an autocrine loop that supports maintenance and cell growth [109]. Todo et al. demonstrated that there is a considerable decrease in meningioma cells proliferation when these cells are given a neutralizing antibody against PDGF-BB. They saw a similar but less potent behavior when an anti-PDGF-AA antibody, also suggesting that the PDGF-BB pathway is the most important for meningioma maintenance [110].

Imatinib, a potent PDGF inhibitor currently used in different conditions (mainly chronic myeloid leukemia), has also been proven in MN patients. Imatinib possess a very low IC50 of 0.1 μM, this is especially important in MN as the bloodbrain-barrier might decrease the flux of imatinib and other drug particles into the brain. In the NABTC 01–08 study, 23 patients with MN were enrolled, with 13 patients bearing low grade tumors, five with atypical MN and five with anaplastic MN. Response was only evaluated in 19 patients from whom 10 patients experienced disease progression. The rest of the patients remained disease stable. Median PFS was only 2 months, with a PFS6 of 29.4%. When analyzed separately, PFS for grade I MN was 3 months and PFS6 was as high as 45%. In the case of high-grade MN, PFS was 2 months but PFS6 was 0%.

The current landscape of PDGF inhibition is somewhat promising. Other agents like sunitnib, MLN518, dasatinib, AMN 107, pazopanib, sorafenib, CP673451 and CHIR 265 have been studied [111]. Furthermore, combination therapies using imatinib and other different agents like hydroxyurea [112], which has showed some benefit in the treatment of glioblastoma in a Phase I/II trial [113].

#### **8. mTOR inhibitors**

The mTORC1 (mammalian target of rapamycin complex 1) pathway has been reported to interact with merlin as a negative regulator of cell growth control [114]. mTOR is a serine/threonine kinase involved in cell signaling controlling transcription, actin cytoskeleton organization, translational activation, and metabolism in response to environmental cues [9]. The protein exists in two distinct multiprotein complexes. The rapamycin-sensitive complex mTORC1 regulates cell growth and proliferation in response to growth factors and metabolic conditions, whereas the rapamycin-insensitive mTORC2 regulates locally restricted growth processes within a cell and is involved in cell migration. Merlin was shown to enhance the kinase activity of mTORC2 [115].

Previously, Pachou et al. [116] found that mTORC1 is activated in the majority of MNs (7–10%) and that systemic mTORC1 inhibition can impair meningioma tumor formation in vivo. In addition, Akt is well known to be an upstream element of mTORC1 and to be activated in meningioma cells by platelet-derived growth factor [117]. PDGF also induces phosphorylation of p70S6K, the expression of which was reported to be increased in malignant MNs [118].

Several groups analyzed the biological effects of everolimus and temsirolimus on meningioma cell viability. They could clearly show that both inhibitors were effective in reducing meningioma cell viability and proliferation [114]. Moreover, evidence was found that the NF2 gene status may affect the response to both inhibitors but differentially activated mTOR pathways could not explain this result in isogenic meningioma cell lines with and without merlin expression [119]. Further, octreotide was shown to augment the inhibitory effect on the mTOR pathway in meningioma cell lines because mTOR inhibition increases the hyperphosphorylation of AKT which thereby increases cell proliferation [120].

In 2020, Graillon et al. reported the results of the CEVOREM trial, a phase II open label study that evaluated the combination of everolimus and octreotide in 20 high-grade MNs patients. Furthermore, four patients harbored NF2 germline mutation [121]. The overall PFS6 was 55% (95% CI 31.3–73.5%), and 6- and 12-month OS rates were 90% (95% CI 65.6–97.4%) and 75% (95% CI 50.0–88.7%), respectively. A decrease >50% was observed in the growth rate at 3 months in 78% of tumors. In addition, the median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (*p* < 0.0002) and 0.48%/3 months at 6 months after treatment (*p* < 0.0003) [120].

In a small trial, everolimus has also been studied in conjunction with bevacizumab without finding any objective tumor response but showing a slight increase in PFS for those with high-grade MNs (NCT00972335) [122]. In this study, 88% of the 18 patients showed SD for a median duration of 10 months (2–29 months). Nevertheless, overall median PFS was 22 months (95% CI 4.5–26.8), higher for patients with WHO grade II and III than grade I tumors (22.0 months vs. 17.5 months). Four patients discontinued treatment due to toxicity (proteinuria, 2; colitis, 1, thrombocytopenia, 1), but another grade 3 toxicity was uncommon, and no patient had grade 4 toxicity. The interesting improvement in higher histological grade MNs could be due to their increased vasculature and the increased dependence on the mTOR pathway of these lesions [122].

There is currently a phase 0, single group assignment, trial for everolimus in NF2 mutant MNs and vestibular schwannomas (NCT01880749). There are two single group assignment phase II trials of another mTOR inhibitor, AZD2014; NCT03071874 for recurrent grade II/III MNs and NCT02831257 for NF2 patients with MNs. These trials will help determine the efficacy of mTOR inhibition in patients with these challenging lesions. Besides, a case report of a female patient

with metastatic meningotheliomatous meningioma involving the brain and the lung was treated with the pan-AKT inhibitor, AZD5363 for AKT1E17K mutation, showed a favorable and durable response [123]. Ex vivo cultured meningioma cells revealed sensitivity to the drug as shown by pan-AKT accumulation on immunoblots. The patient has been treated for more than a year with a response which warrants further research [123].
