Innovative Therapeutic Strategies in the Treatment of Meningioma

Current Treatments

Surgery. Meningiomas grow by expanding, leading to compression of the adjacent structures (7). For symptomatic or progressively enlarging meningiomas, complete surgical excision of the tumor bulk, and surrounding dural attachment, is recommended. Prognostic variables predictive of survival in patients with meningiomas include the extent of resection, histological grade, patient's age, and tumor location. The completeness of surgical removal is an important prognostic feature (8). The best accepted factor for prediction of recurrence is the Simpson grading system, which evaluates invasion of the venous sinuses, tumor nodules in adjacent dura, and infiltration of bone by meningothelial cells as chief causes for recurrence (9). Patients with a Simpson grade 1 (complete removal) meningioma have a 10-year recurrence rate of 9% compared to patients with a Simpson grade 3 (complete removal, without coagulation of dural attachment or resection of involved sinus or hyperostotic bone) meningioma, for whom the 10-year recurrence rate is about 29%. Kinjo et al. classified a more extensive resection as “grade zero”, requiring gross total resection of the primary, any hyperostotic bone, and all involved dura with a 2 cm dural margin (10).

More factors may represent probable causes of recurrence in meningiomas. Extent of tumor resection, histological type and WHO grade, and brain invasion are prognostic factors of meningioma recurrence. Sphenoid wing and parasagittal meningiomas recur most frequently because of their location and sinus attachments. The presence of remaining meningotheliomatous cells on dural strips or the presence of neoplastic dural cells around the site of craniotomy, might be reasons for recurrence (11, 12). The possibility of a correlation between genetic and immunohistochemical markers and meningioma recurrence is highly intriguing. Genes of histone cluster 1 on 6p, as well as genes cyclin B1 (CCNB1) and marker of proliferation Ki-67 (MKI67) were shown to be overexpressed in recurrent meningiomas (13, 14). More, chromosomal aberrations associated with higher-grade meningioma include 1p, 6q, 10p, 10q, 14q, and 18q (15). Other markers that have been reported to correlate with higher-grade meningioma include the B-cell lymphoma 2 (BCL2) proto-oncogene, p53, p51, alterations in tumor-suppressor genes, the apoptosis antigen 1 (FAS receptor or APO1) transmembrane protein, the extracellular matrix protein tenascin, and five novel meningioma-expressed antigens (15-17). Immunohistochemical staining with the MIB-1 antibody (Ki-67) has consistently correlated with meningioma recurrence (18). Vascular endothelial growth factor (VEGF) has also been associated with recurrence due to increased neovascularization (19). Osteopontin, a factor regulating several processes in tumor progression, is more highly expressed in recurrent compared to non-recurrent meningiomas and in grade II compared with grade I meningiomas (20). However, subtotal resection alone remains common in practice, and in some series of patients with 10 to 20 years of follow-up, the 5-, 10-, and longer than 15-year progression rates following subtotal resection were 37 to 47%, 55 to 63%, and greater than 70%, respectively (21).

Radiation therapy. The role of surgery alone, especially for atypical and malignant meningiomas, can sometimes be unsuccessful. Factors considered in the decision to use radiation therapy include the extent of resection, grade, and histological subtype, as well as age (in the case of pediatric meningiomas).

Several types of external-beam radiation exist, including modern approaches such as photon-based stereotactic radiosurgery and hypofractionated radiation therapy. Treatment plans may be directed to the remaining lesion following subtotal resection, or the resection cavity plus a margin of approximately 1 cm following gross total resection of higher grade tumors. Preliminary observational studies have demonstrated that immediate postoperative radiation improves the outcomes in patients with WHO grade II and III meningiomas (22). Aghi and colleagues, in a series of 108 patients with atypical meningiomas who underwent gross total resection, showed that immediate postoperative radiation reduces local tumor recurrence and improves survival of patients (23). Radiation necrosis, exacerbation of peritumoral edema and cranial nerve palsy are the principle complications observed in patients undergoing radiation therapy (22).

Radiosurgery. Radiosurgery can represent an effective primary or adjunctive treatment for grade I meningiomas located in regions where aggressive resection carries a high risk of operative morbidity (24, 25). Radiosurgery also represents a valid option for recurrent or partially resected meningiomas less than 35 mm in diameter (26, 27). On the other hand, the role of radiosurgery in the treatment of grade II and III meningiomas is not well-established, and the outcomes of patients treated with radiosurgery reported in various studies are not yet well-defined. The validity of radiosurgical treatment in patients affected by grade II and III meningiomas is still an object of debate due to the large number of variables minored such as tumor features, patient characteristics and type of outcome scale adopted. However, in an interesting review, characterized by a cohort of grade II and III meningiomas treated with radiosurgery, the authors demonstrated a progression-free survival (PFS) rate at 5 years of 25-83% (median 59%) for those with grade II tumors and 0%-72% (median 13%) for those with grade III tumors (24). Prospective clinical trials evaluating the risk-benefit profile of conservative management, external-beam radiation therapy and radiosurgery in the setting of residual and recurrent disease are necessary (28). However, due to the relatively low prevalence of grade II and III meningiomas compared to grade I tumors, it is unlikely that a prospective trial will be able to accrue a statistically adequate number of patients.

Cytotoxic agents. Chemotherapeutic agents target specific pathophysiological pathways and molecular mechanisms that control various processes including cellular differentiation, cell proliferation, angiogenesis, and apoptosis. However, chemotherapeutic treatment is limited by poor understanding of the molecular pathogenesis of meningiomas, as well as by the lack of tumor models and pre-clinical studies.

Numerous conventional cytotoxic agents, including temozolomide, hydroxyurea, imatinib, trabectedin, and irinotecan have been studied over the years for treatment of meningiomas. However, results from clinical trials have generally been disappointing (29).

In a phase II study, temozolomide was administered at a dose of 75 mg/m²/day for 42 days every 10 weeks, to 16 patients affected by refractory meningiomas. None of the 16 enrolled patients experienced a complete or partial radiological response to therapy (30). Subsequently, de Robles et al. demonstrated the role of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase in limiting the therapeutic potential of temozolomide (31).

Hydroxyurea is an oral ribonucleotide reductase inhibitor that arrests the cell cycle in the S-phase and induces apoptosis. In a preliminary report, hydroxyurea reduced tumor size in three patients with recurrent benign meningiomas, and prevented recurrent disease for 24 months in a patient after complete resection of malignant meningioma (32). A follow-up retrospective study of 35 patients with WHO grade II and III meningiomas showed 57% of patients to have progression of disease at 6 months, showing a low efficacy of hydroxyurea in tumor control (33). The activity of hydroxyurea is now being studied in association with other compounds. Calcium channel antagonists (CCAs), such as verapamil and diltiazem, can block the stimulatory effects of numerous growth factors on meningioma cell culture and augment the growth inhibitory effects of hydroxyurea (34, 35). An experimental study demonstrated the effectiveness of CCAs with hydroxyurea and RU486 (mifepristone) in a xenograft mouse meningioma tumor model, with decreased cellular proliferation and vascular density (34). Furthermore, it has been shown that CCAs block the mitogenic effects of various growth factors, induce G₁ cell-cycle arrest, and augment the growth inhibitory effects of both hydroxyurea and RU486 (35). Recently, Reardon et al. examined the activity of imatinib plus hydroxyurea in a phase II trial of 21 patients with progressive/recurrent meningiomas. The primary end-point was PFS at 6 months and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). Imatinib plus hydroxyurea was well-tolerated but showed a modest antitumor activity (36). Negligible activity of imatinib was evident in another series of 23 patients with recurrent/progressive meningioma (37). No radiographic responses to imatinib monotherapy were observed and PFS at 6 months was only 29.4% (37).

Trabectedin was investigated in a pre-clinical study published by Preusser et al., and demonstrated a statistically significant response to treatment of various meningioma cell lines. The activity of trabectedin was tested against primary cell cultures obtained from surgical meningioma samples. A favorable clinical benefit was observed in cell cultures from a patient with advanced anaplastic meningioma and extensive tumor recurrence (38).

An experimental study evaluated the activity of the topoisomerase I inhibitor irinotecan (CPT-11) on primary meningioma cultures and a malignant meningioma cell line in vitro and in vivo. Irinotecan induced a dose-dependent anti-proliferative effect with apoptosis in the primary meningioma cultures, as well as in the IOMM-Lee human malignant meningioma cell line. In the animal model, irinotecan treatment led to a statistically significant decrease in tumor growth and an increase in apoptotic cell death (39).

Curic et al. described a dose-dependent response of meningioma cell lines exposed to curcumin, component of the spice plant Curcuma longa, which is known to have anti-tumorigenic properties (40). Park et al. also demonstrated a potent cytotoxic effect of acetyl-11-keto-beta-boswellic acid, a substance isolated from the gum resin of Boswellia serrata trees, on 11 primary cell lines derived from human meningioma resections. This class of boswellic acid drugs is believed to work by inhibition of microsomal prostaglandin E synthase-1 and the serine protease cathepsin G (41).

Targeted Therapies

Targeted therapies block activation of oncogenic pathways, either at the ligand-receptor interaction level or by inhibiting downstream signal transduction pathways, thereby inhibiting growth and progression of cancer (42, 43). Because of their specificity, targeted therapies should theoretically have better efficacy and safety profiles than systemic cytotoxic chemotherapy or radiotherapy. The pathogenesis and molecular genetics of meningiomas are not well known, and a large number of chromosomal, signaling pathways and growth factor alterations have been reported. Several genes have been identified as targets for mutation or inactivation. Additional chromosomal regions have been found to be commonly deleted or amplified, suggesting the presence of further tumor-suppressor genes or proto-oncogenes in these regions (44). Many genetic factors and pathways have been associated with the proliferation, progression, and recurrence of meningiomas.

Growth factor pathways. A wide variety of growth factors have been implicated in the biology of meningiomas. These include platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factors α (TGFα) and β (TGFβ), stromal cell-derived growth factor B, and bone morphogenetic proteins. PDGF and EGF play a critical role in the activation of main anti-apoptotic cell signaling pathways [rat sarcoma (RAS)/mitogen-activated protein kinase (MAPK)] and phosphoinositide 3 kinase–protein kinase B (PI3K–AKT) and of a secondary pathway phospholipase C-γ1-protein kinase C (45). Activating PI3K leads to AKT phosphorylation and p70 (S6K) activation by way of mammalian target of rapamycin (mTOR). High levels of phosphorylated AKT are found in atypical and anaplastic meningiomas. Inhibition of this pathway with selective mitogen activated protein kinase kinase 1 (MEK1) inhibitors has shown reduced MAPK activity and inhibition in meningioma cell cultures (45). Farnesyl transferase inhibitors, a class of chemotherapeutic agents that block farnesyl transferase, thereby inhibiting RAS localization and activation to the cytoplasmic surface of the receptor are under investigation (45).

The invasiveness of neoplastic cells of human meningiomas has been related to expression of matrix-metalloproteinase-9, a peptidase actively implicated in the degradation of the extracellular matrix (46). A plasmid vector was used to transfect meningioma cells in vitro and in vivo with complementary double-stranded RNA to cathepsin B and matrix-metalloproteinase-9 mRNA. Decreased expression of these enzymes, associated with a significant reduction of meningioma migration and invasiveness, was observed (47). Merlin is a member of the erzin-radixinmoesin family of proteins and interacts with the intermolecular amino-terminal domain and the carboxyl-terminal domain through phosphorylation. The functions of merlin are not well understood, but it is believed that they involve regulation of cell proliferation pathways, which have a prominent role in meningioma propagation. Expression of NF2 and merlin inactivation varies among WHO grade I meningioma subtypes (48).

The PI3K pathway is the parallel pathway by which meningioma induction and propagation via growth factor effects are mediated. PI3K catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to PIP 3,4,5-trisphosphate (PIP3), a reaction that is controlled and inhibited by phosphatase and tensin homolog (PTEN). PIP3 activates AKT protein, which in turn activates mTOR (49). Pachow et al. recently demonstrated significant reductions in meningioma cell growth in mouse models treated with the mTOR inhibitor drugs temsirolimus and everolimus (50).

The EGF receptors (EGFRs) are overexpressed in up to 60% of meningiomas. These receptors stimulate the MAPK and PI3K pathways. An interesting study showed that treatment with EGFR inhibitors gefitinib (64%) or erlotinib (36%) in 25 patients with refractory meningiomas did not result in significant benefits (51). Other agents that inhibit EGFR alone, or together with other receptor tyrosine kinases may have therapeutic potential activity against meningiomas. For instance, lapatinib inhibits EGFR and human epidermal growth factor receptor 2, HKI-272 inhibits all subtypes of the EGFR, and ZD6474 inhibits EGFR and VEGFR. Humanized monoclonal antibodies to EGFR, including cetuximab, panitumumab, matuzumab, EMD 72000, mAb 806, and nimotuzumab are being investigated (52-55). In a phase I study of a murine monoclonal antibody against EGFR in nine patients with either glioma or meningioma, treatment was well tolerated, but no radiographic responses were detected (56).

VEGF and VEGFRs mediate angiogenesis in various types of brain tumors (57). VEGF is up-regulated in meningiomas (58) even if, Barresi and Tuccari showed the absence of correlation between VEGF expression and WHO tumor grade (59). Additionally, VEGF plays an important role in the formation of peritumoral edema, which adds to the morbidity associated with these tumors. Bevacizumab is a monoclonal antibody that binds VEGFB inhibiting angiogenesis. Inhibition of VEGF by bevacizumab also affects the tumor vasculature, suppressing new blood vessel growth and the existing vasculature (60). Underlying mechanisms of angiogenesis inhibition include a direct antitumor effect, endothelial cell radiosensitization resulting in damaged tumor vasculature, and improved oxygenation as a result of elimination of tumor vessels and decrease in interstitial pressure (61). In a retrospective review by Lou et al., the utility of bevacizumab-based therapy for recurrent/progressive meningiomas was evaluated. They suggested that bevacizumab led to a response in recurrent meningioma (62). In a recent study about the use of bevacizumab in patients with NF2, the authors disclosed the significant expression of SEMA3, an angiogenesis inhibitor, and the absence of any correlation between expression of VEGF pathway components and tumor microvascular density. The same authors affirmed that the effects of bevacizumab on meningiomas were not clear and the relative effect on response was small, and likely not clinically relevant (63). Additionally, there are currently several ongoing trials incorporating VEGF/VEGFR-directed therapy for patients with recurrent, progressive meningioma, including a multicenter phase II trial combining bevacizumab with the mTOR inhibitor everolimus, and separate phase II study evaluating bevacizumab as single agent (NCT00972335 and NCT01125046).

PDGFB is another crucial factor that promotes the recruitment and proliferation of vascular cells. It can induce the transcription and secretion of VEGF. PDGFB and PDGFRB are expressed in meningiomas, and their overexpression correlates with the WHO grade (64). Pfister et al. recently tested the effects of gambogic acid and two tyrosine kinase inhibitors of PDGFRB (sunitinib and tandutinib) on meningiomas in vitro, concluding that these PDGFRB inhibitors inhibit the migration of meningioma cells in vitro (65). Imatinib mesylate (Gleevec) is an inhibitor of PDGFRA and -B, FMS-related tyrosine kinase 1 (FLT1), and tyrosine-proyein kinase (KIT). Two phase II trials have been reported on the use of imatinib alone and in combination with hydroxyurea, enrolling 23 and 21 patients, respectively. As a single-agent, imatinib was well-tolerated but had no significant activity against recurrent meningiomas. PFS at 6 months for patients with benign meningiomas was 45%, and for those with atypical and malignant meningiomas, it was 0% (66, 67). A recent study evaluated the efficacy of sunitinib in 36 patients with malignant meningioma. The PFS rate was 42%, meeting the primary end-point of the study (68). Gupta et al. reported that nelfinavir, an anti-retroviral drug, can strengthen the efficacy of imatinib therapy (69). Similarly, Johnson et al. described reduced meningioma growth in cell lines exposed to lopinavir, another antiretroviral drug (70). Second-generation PDGF inhibitors such as nilotinib or dasatinib, which are thought to be more potent inhibitors have not been tested on meningioma cells.

In 2006, a study concerning transfection of tissue factor pathway inhibitor 2 (TFPI2) mRNA in the malignant meningioma cell line IOMM-Lee evaluated tumor growth in vitro and in vivo suggested that TFPI2 could have therapeutic potential in malignant meningioma (71). Recently, Wilisch-Neumann et al. published a study concerning the impact of the cilengitide, an inhibitor of α_vβ₅ integrins, on migration, proliferation, and radiosensitization of meningioma cells, analyzing integrin expression in tissue microarrays of human meningiomas and in cell cultures, and subcutaneous and intracranial nude mouse models. The data showed that cilengitide is not likely to achieve major responses against rapidly growing malignant meningiomas, although brain invasion may be reduced because of the strong antimigratory properties of the drug. Its combination with radiotherapy deserved further attention (72).

Tumor-suppressor proteins. A family of membrane-bound proteins known as the Band 4.1 family has been discovered on the cytoplasmic side of the cell membrane (73). Genetic mutations that lead to abnormal function of these proteins are believed to be one of the main causes for meningioma development. Gutmann et al. showed that loss of protein 4.1B appears to be similarly distributed among meningioma grades, again suggesting this to be an early event in the formation of meningiomas (74). Protein 4.1B was revealed to interact with the cell growth regulator protein 14-3-3. Although aggressive meningiomas show reduced levels of 14-3-3 expression, impaired 14-3-3 function has not been shown to affect protein 4.1B function, suggesting that alternative signaling pathways are present (5).

Liu and colleagues studied the expression and role of periostin in meningiomas (75). It seems that periostin and Ki-67 may play a role in predicting the grade and prognosis of meningiomas. Drugs targeting periostin aim at reducing invasion of meningiomas (75). Recently, Zhang et al. disclosed the existence of five genes [NF2, meningioma 1 (MN1), AT rich interactive domain 1B (ARID1B), sema domain (SEMA4D), and mucin 5 (MUC5)] that carry novel protein-altering variations that can be associated with progression of meningioma. They also documented the candidate genes, NF2 and MN1 to be associated with malignant meningioma (75). Recently Burns et al. reported that in vitro AR-42, a pan-histone deacetylase inhibitor, inhibited proliferation of both Ben-Men-1 and normal meningeal cells by increasing expression of p16 (INK4A), p21(CIP1/WAF1), and p27(KIP1) (72). AR-42 reduced the levels of cyclins D1, E and A, and proliferating cell nuclear antigen in meningeal cells while significantly reducing the expression of cyclin B, important for progression through the G₂ phase in Ben-Men-1 cells. The differential effect of AR-42 on cell-cycle progression of normal meningeal and meningioma cells may have therapeutic implications (76).

Other Systemic Therapies

Estrogen and progesterone receptor antagonists. Hormonal therapies have received considerable interest following the observation of the high incidence of meningioma in women of reproductive age and the discovery that up to two-thirds of meningiomas express progesterone and androgen receptors (4). In addition, several epidemiological studies have suggested that administration of estrogens and progestins affect women's risk of developing meningioma (77, 78). A phase II study including 19 patients with non-resectable refractory meningiomas showed no efficacy benefit of tamoxifen, an estrogen receptor antagonist, in the inhibition of meningioma growth (79). These findings are possibly due to the relatively infrequent estrogen receptor expression in meningioma. Because of the higher likelihood of progesterone receptor expression in meningiomas, several studies evaluated the role of progesterone receptor antagonists as possible candidate drugs. Initial studies of the anti-progesterone mifepristone (RU486) were promising (80, 81). However, their findings were refuted by a large, prospective multi-center, randomized phase III clinical trial enrolling 180 patients which failed to show any major benefit of mifepristone over placebo (82). These findings might be explained by the fact that this study enrolled patients with meningioma subtypes characterized by reduced expression of progesterone receptors. A recent trial evaluating mifepristone in a pre-selected population with diffuse meningiomatosis highly expressing progesterone receptor demonstrated a significant long-lasting clinical and radiological response or stabilization (83). Taken together, these studies suggest that potential sub-groups of patients with meningioma are more likely to benefit from mifepristone and support its use in further prospective clinical trials of preselected populations.

Somatostatin receptor agonists. Somatostatins (SSTs) are a family of neuropeptides produced in the hypothalamus involved in a wide range of physiological processes, including neuromodulation and inhibition of secretory processes and cell proliferation (84). Meningiomas are known to have a high frequency of somatostatin receptor expression (up to 90%), especially of the SST2A sub-type, although their functional role remains unclear. Experimental and human studies have evaluated the effect of somatostatin and somatostatin analogs on meningioma growth, with contradictory results (85, 86). A prospective pilot trial of a long-acting somatostatin analog agonist (Sandostatin LAR®) reported a partial radiographic response in 31% of patients with recurrent meningiomas and the PFS at 6 months was 44% (87). Pasireotide (SOM230), a novel long-acting somatostatin analog, has a wider somatostatin receptor spectrum (including sub-types 1, 2, 3, and 5) and has a higher affinity than octreotide. A recently completed randomized phase II clinical trial was designed to evaluate whether pasireotide LAR (SOM230C) prolongs PFS at 6 months in patients with recurrent or progressive meningioma. The study demonstrated that it has limited activity against recurrent meningioma (88).

Interferon-α 2B (IFNα). IFNα is a leukocyte-produced cytokine that has been shown to inhibit meningioma cells in vitro. Very few studies were published that used IFNα for recurrent meningioma showing a modest effect (89, 90). The largest such study was published by Chamberlain and Glantz in 2008 (91). Thirty-five patients with recurrent meningiomas were enrolled. Although the patients did not demonstrate a significant partial or complete radiographic response, IFNα had cytostatic activity, achieving meaningful palliation, as reflected by a 6-month PFS rate of 54%.

MicroRNA. MicroRNAs (miRNAs) are a group of short (from 21- to 23) nucleotides that control the expression of many target genes at the post-transcriptional level. They are aberrantly expressed in many types of cancer and play a major role in regulating a large number of pathways. Therapeutic strategies can include direct tumor-suppressive effects, anti-angiogenic effects, anti-metastatic effects, suppression of immune evasion of tumors, and sensitization of tumor cells to classical anticancer treatments. Recent data suggest that the use of miRNA profiling has significant potential as an effective diagnostic and prognostic tool in defining the expression signature of meningiomas. Down-regulation of miR-29c-3p and miR-219-5p were found to be associated with advanced clinical stages of meningioma. In addition, these data showed that high expression of miR-190a and low expression of miR-29c-3p and miR-219-5p correlated significantly with higher recurrence rates in patients with meningioma (92). A recent research study demonstrated a valid antimigratory and antiproliferative function of miR-145 against meningiomas (93). Overexpression of miR-145 in IOMM-Lee meningioma cells resulted in reduced proliferation, increased sensitivity to apoptosis, and reduction of orthotopic tumor growth in nude mice. Moreover, meningioma cells with high miR-145 levels had impaired migratory and invasive potential both in vitro and in vivo (94). A novel experimental study has demonstrated a key role for miR-200a down-regulation in promoting the growth of meningiomas. Reduced levels of miR-200a appear to contribute to tumorigenesis through two pathways mediated by up-regulation of three mRNA targets (94). Recent data confirmed that elevated levels of miR-335 increased cell growth and inhibited cell cycle arrest in the G₀/G₁ phase in vitro. It is probably that miR-335 plays an essential role in the proliferation of meningioma cells by directly targeting the retinoblastoma gene 1 (Rb1) signaling pathway (95).