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ANTICANCER RESEARCH 35: 6391-6400 (2015)

Review Innovative Therapeutic Strategies in the Treatment of

GERARDO CARUSO1, SAMER K. ELBABAA2, PABLO GONZALEZ-LOPEZ3, VALERIA BARRESI4, MARCELLO PASSALACQUA1 and MARIA CAFFO1

1Neurosurgical Clinic, Department of Neuroscience, and 4Department of Human Pathology, University of Messina, Messina, Italy; 2Department of Neurological Surgery, Saint Louis University School of Medicine, Saint Louis, MO, U.S.A.; 3Department of Neurosurgery, University Hospital Alicante, Miguel Hernandez University School of Medicine, Alicante, Spain

Abstract. Few medical options are available for progressive/ (NF2) on chromosome 22q12.2. This gene encodes the recurrent and atypical/anaplastic . New merlin structural protein of the membrane. Typically, developments in chemotherapeutic options for meningiomas individuals with NFT2 develop multiple meningiomas. have been explored over the past decade. We review the more About 90% of meningiomas are classified according to the recent literature to recognize studies investigating recent World Health Organization (WHO) grading system as WHO medical and chemotherapeutic agents that have been grade I (2). This group includes meningothelial, fibroblastic experienced or are currently being tested for meningiomas. and transitional meningiomas. WHO grade I meningiomas Combination therapies affecting multiple molecular targets are generally defined as benign, but, for these histotypes, are currently opening up and present significant promise as recurrence rates are in the range of 7-20% and these have a adjuvant therapeutic options. However, there is an evident clear possibility of progression to higher grades. Atypical need for new molecular studies in order to better understand meningiomas WHO grade II include 5-15% of all the biology of meningiomas and, thus, to identify new and meningiomas (3). These lesions present recurrence rates of more specific therapeutic targets. 30-40% (3). Chordoid and clear cell meningiomas have an aggressive course, with a high rate of recurrence, and are Meningiomas are the most common primary intracranial classified as grade II (4). Anaplastic or malignant , constituting over one-third of all brain tumors (1). meningiomas are classified as WHO grade III and account Meningiomas arise from arachnoidal cells of the for 1-3% of cases (3). Grade III tumors have higher leptomeninges and may occur wherever arachnoidal cells are frequencies of local invasion, recurrence, and . located. The origin of meningioma is yet to be determined. The treatment of choice for benign meningiomas is Certainly radiation therapy used in the treatment of brain represented by total surgical resection, resulting in prolonged tumors is associated with an increased risk of meningioma. disease-free survival (5). Conversely, atypical and malignant Moreover, the presence of progesterone and estrogen meningiomas frequently recur and are associated with a receptors denotes a possible link between the development shorter overall survival (6). Treatment options for recurrence of meningioma and sex hormones. type 2 or incomplete resection include further surgery, conventional (NFT2) is an autosomal-dominant disorder characterized by external beam irradiation, stereotactic radiosurgery and mutations of the neurofibromin 2 systemic therapies. To date, and hormonal therapies have had only a very limited role and have been shown to be generally ineffective. Radiation therapy or stereotactic radiosurgery is limited by radiation neurotoxicity, Correspondence to: Gerardo Caruso, MD, Via Consolare Valeria no. tumor size, and injury to adjacent vascular or cranial nerves. 1, 98124, Messina, Italy. Tel: +39 0902217167, Fax: +39 090693714, e-mail: [email protected] Over the past decades, the use of systemic therapies in the treatment of meningiomas has been the subject of intense Key Words: Meningioma, nanomedicine, surgery, targeted therapies, research and novel promising drugs with therapeutic treatment, review. potential are now being tested in an increased number of

0250-7005/2015 $2.00+.40 6391 ANTICANCER RESEARCH 35: 6391-6400 (2015) clinical trials. Recently nanomedicine, the application of Genes of histone cluster 1 on 6p, as well as genes cyclin B1 nanotechnology to health care, holds great promise for (CCNB1) and marker of proliferation Ki-67 (MKI67) were revolutionizing medical treatments, imaging, drug delivery, shown to be overexpressed in recurrent meningiomas (13, and tissue regeneration. Nanoparticle systems in 14). More, chromosomal aberrations associated with higher- therapies provide better penetration of therapeutic and grade meningioma include 1p, 6q, 10p, 10q, 14q, and 18q diagnostic agents, and a reduced risk in comparison to (15). Other markers that have been reported to correlate with conventional treatments. By using nanotechnology, it is higher-grade meningioma include the B-cell lymphoma 2 possible to deliver the drug to the targeted tissue and release (BCL2) proto-, p53, p51, alterations in tumor- the drug at a controlled rate. suppressor genes, the 1 (FAS receptor or Herein, we review the current literature for therapeutic APO1) transmembrane protein, the extracellular matrix approaches for meningiomas. In particular, after discussing protein tenascin, and five novel meningioma-expressed the standard therapy for meningiomas, including surgery and (15-17). Immunohistochemical staining with the radiation therapy, we focus on novel therapeutic strategies in MIB-1 antibody (Ki-67) has consistently correlated with the treatment of recurrent and malignant meningiomas, meningioma recurrence (18). Vascular endothelial growth highlighting the emerging role of targeted molecular factor (VEGF) has also been associated with recurrence due therapies. to increased neovascularization (19). Osteopontin, a factor regulating several processes in tumor progression, is more Current Treatments highly expressed in recurrent compared to non-recurrent meningiomas and in grade II compared with grade I Surgery. Meningiomas grow by expanding, leading to meningiomas (20). However, subtotal resection alone remains compression of the adjacent structures (7). For symptomatic common in practice, and in some series of patients with 10 or progressively enlarging meningiomas, complete surgical to 20 years of follow-up, the 5-, 10-, and longer than 15-year excision of the tumor bulk, and surrounding dural progression rates following subtotal resection were 37 to attachment, is recommended. Prognostic variables predictive 47%, 55 to 63%, and greater than 70%, respectively (21). of survival in patients with meningiomas include the extent of resection, histological grade, patient’s age, and tumor Radiation therapy. The role of surgery alone, especially for location. The completeness of surgical removal is an atypical and malignant meningiomas, can sometimes be important prognostic feature (8). The best accepted factor for unsuccessful. Factors considered in the decision to use prediction of recurrence is the Simpson grading system, radiation therapy include the extent of resection, grade, and which evaluates invasion of the venous sinuses, tumor histological subtype, as well as age (in the case of pediatric nodules in adjacent dura, and infiltration of bone by meningiomas). meningothelial cells as chief causes for recurrence (9). Several types of external-beam radiation exist, including Patients with a Simpson grade 1 (complete removal) modern approaches such as photon-based stereotactic meningioma have a 10-year recurrence rate of 9% compared radiosurgery and hypofractionated radiation therapy. to patients with a Simpson grade 3 (complete removal, Treatment plans may be directed to the remaining lesion without coagulation of dural attachment or resection of following subtotal resection, or the resection cavity plus a involved sinus or hyperostotic bone) meningioma, for whom margin of approximately 1 cm following gross total resection the 10-year recurrence rate is about 29%. Kinjo et al. of higher grade tumors. Preliminary observational studies classified a more extensive resection as “grade zero”, have demonstrated that immediate postoperative radiation requiring gross total resection of the primary, any improves the outcomes in patients with WHO grade II and hyperostotic bone, and all involved dura with a 2 cm dural III meningiomas (22). Aghi and colleagues, in a series of 108 margin (10). patients with atypical meningiomas who underwent gross More factors may represent probable causes of recurrence total resection, showed that immediate postoperative in meningiomas. Extent of tumor resection, histological type radiation reduces local tumor recurrence and improves and WHO grade, and brain invasion are prognostic factors of survival of patients (23). Radiation necrosis, exacerbation of meningioma recurrence. Sphenoid wing and parasagittal peritumoral edema and cranial nerve palsy are the principle meningiomas recur most frequently because of their location complications observed in patients undergoing radiation and sinus attachments. The presence of remaining therapy (22). meningotheliomatous cells on dural strips or the presence of neoplastic dural cells around the site of craniotomy, might be Radiosurgery. Radiosurgery can represent an effective reasons for recurrence (11, 12). The possibility of a primary or adjunctive treatment for grade I meningiomas correlation between genetic and immunohistochemical located in regions where aggressive resection carries a high markers and meningioma recurrence is highly intriguing. risk of operative morbidity (24, 25). Radiosurgery also

6392 Caruso et al: Meningioma Treatment (Review) represents a valid option for recurrent or partially resected showing a low efficacy of hydroxyurea in tumor control (33). meningiomas less than 35 mm in diameter (26, 27). On the The activity of hydroxyurea is now being studied in other hand, the role of radiosurgery in the treatment of grade association with other compounds. Calcium channel II and III meningiomas is not well-established, and the antagonists (CCAs), such as verapamil and diltiazem, can outcomes of patients treated with radiosurgery reported in block the stimulatory effects of numerous growth factors on various studies are not yet well-defined. The validity of meningioma cell culture and augment the growth inhibitory radiosurgical treatment in patients affected by grade II and effects of hydroxyurea (34, 35). An experimental study III meningiomas is still an object of debate due to the large demonstrated the effectiveness of CCAs with hydroxyurea number of variables minored such as tumor features, patient and RU486 (mifepristone) in a xenograft mouse meningioma characteristics and type of outcome scale adopted. However, tumor model, with decreased cellular proliferation and in an interesting review, characterized by a cohort of grade vascular density (34). Furthermore, it has been shown that II and III meningiomas treated with radiosurgery, the CCAs block the mitogenic effects of various growth factors, authors demonstrated a progression-free survival (PFS) rate induce G1 cell-cycle arrest, and augment the growth at 5 years of 25-83% (median 59%) for those with grade II inhibitory effects of both hydroxyurea and RU486 (35). tumors and 0%-72% (median 13%) for those with grade III Recently, Reardon et al. examined the activity of tumors (24). Prospective clinical trials evaluating the risk- plus hydroxyurea in a phase II trial of 21 patients with benefit profile of conservative management, external-beam progressive/recurrent meningiomas. The primary end-point radiation therapy and radiosurgery in the setting of residual was PFS at 6 months and secondary endpoints were safety, and recurrent disease are necessary (28). However, due to radiographic response rate, and overall survival (OS). Best the relatively low prevalence of grade II and III radiographic response was stable disease and was observed meningiomas compared to grade I tumors, it is unlikely that in 14 patients (67%). Imatinib plus hydroxyurea was well- a prospective trial will be able to accrue a statistically tolerated but showed a modest antitumor activity (36). adequate number of patients. Negligible activity of imatinib was evident in another series of 23 patients with recurrent/progressive meningioma (37). Cytotoxic agents. Chemotherapeutic agents target specific No radiographic responses to imatinib monotherapy were pathophysiological pathways and molecular mechanisms that observed and PFS at 6 months was only 29.4% (37). control various processes including cellular differentiation, Trabectedin was investigated in a pre-clinical study cell proliferation, , and apoptosis. However, published by Preusser et al., and demonstrated a statistically chemotherapeutic treatment is limited by poor understanding significant response to treatment of various meningioma cell of the molecular pathogenesis of meningiomas, as well as by lines. The activity of trabectedin was tested against primary the lack of tumor models and pre-clinical studies. cell cultures obtained from surgical meningioma samples. A Numerous conventional cytotoxic agents, including favorable clinical benefit was observed in cell cultures from temozolomide, hydroxyurea, imatinib, trabectedin, and a patient with advanced anaplastic meningioma and extensive irinotecan have been studied over the years for treatment of tumor recurrence (38). meningiomas. However, results from clinical trials have An experimental study evaluated the activity of the generally been disappointing (29). topoisomerase I inhibitor irinotecan (CPT-11) on primary In a phase II study, temozolomide was administered at a meningioma cultures and a malignant meningioma cell line dose of 75 mg/m2/day for 42 days every 10 weeks, to 16 in vitro and in vivo. Irinotecan induced a dose-dependent patients affected by refractory meningiomas. None of the 16 anti-proliferative effect with apoptosis in the primary enrolled patients experienced a complete or partial meningioma cultures, as well as in the IOMM-Lee human radiological response to therapy (30). Subsequently, de malignant meningioma cell line. In the animal model, Robles et al. demonstrated the role of the DNA repair irinotecan treatment led to a statistically significant decrease enzyme O6-methylguanine-DNA-methyltransferase in in tumor growth and an increase in apoptotic cell death (39). limiting the therapeutic potential of temozolomide (31). Curic et al. described a dose-dependent response of Hydroxyurea is an oral ribonucleotide reductase inhibitor meningioma cell lines exposed to curcumin, component of that arrests the in the S-phase and induces the spice plant Curcuma longa, which is known to have anti- apoptosis. In a preliminary report, hydroxyurea reduced tumorigenic properties (40). Park et al. also demonstrated a tumor size in three patients with recurrent benign potent cytotoxic effect of acetyl-11-keto-beta-boswellic acid, meningiomas, and prevented recurrent disease for 24 months a substance isolated from the gum resin of Boswellia serrata in a patient after complete resection of malignant trees, on 11 primary cell lines derived from human meningioma (32). A follow-up retrospective study of 35 meningioma resections. This class of boswellic acid drugs is patients with WHO grade II and III meningiomas showed believed to work by inhibition of microsomal prostaglandin 57% of patients to have progression of disease at 6 months, E synthase-1 and the serine protease cathepsin G (41).

6393 ANTICANCER RESEARCH 35: 6391-6400 (2015)

Targeted Therapies intermolecular amino-terminal domain and the carboxyl- terminal domain through phosphorylation. The functions of Targeted therapies block activation of oncogenic pathways, merlin are not well understood, but it is believed that they either at the ligand-receptor interaction level or by inhibiting involve regulation of cell proliferation pathways, which have downstream signal transduction pathways, thereby inhibiting a prominent role in meningioma propagation. Expression of growth and progression of cancer (42, 43). Because of their NF2 and merlin inactivation varies among WHO grade I specificity, targeted therapies should theoretically have better meningioma subtypes (48). efficacy and safety profiles than systemic cytotoxic The PI3K pathway is the parallel pathway by which or radiotherapy. The pathogenesis and meningioma induction and propagation via molecular genetics of meningiomas are not well known, and effects are mediated. PI3K catalyzes the conversion of a large number of chromosomal, signaling pathways and phosphatidylinositol 4,5-bisphosphate (PIP2) to PIP 3,4,5- growth factor alterations have been reported. Several genes trisphosphate (PIP3), a reaction that is controlled and have been identified as targets for mutation or inactivation. inhibited by phosphatase and tensin homolog (PTEN). PIP3 Additional chromosomal regions have been found to be activates AKT protein, which in turn activates mTOR (49). commonly deleted or amplified, suggesting the presence of Pachow et al. recently demonstrated significant reductions in further tumor-suppressor genes or proto- in these meningioma cell growth in mouse models treated with the regions (44). Many genetic factors and pathways have been mTOR inhibitor drugs temsirolimus and everolimus (50). associated with the proliferation, progression, and recurrence The EGF receptors (EGFRs) are overexpressed in up to of meningiomas. 60% of meningiomas. These receptors stimulate the MAPK and PI3K pathways. An interesting study showed that Growth factor pathways. A wide variety of growth factors treatment with EGFR inhibitors (64%) or have been implicated in the biology of meningiomas. These (36%) in 25 patients with refractory meningiomas did not include platelet-derived growth factor (PDGF), epidermal result in significant benefits (51). Other agents that inhibit growth factor (EGF), transforming growth factors α (TGFα) EGFR alone, or together with other receptor tyrosine kinases and β (TGFβ), stromal cell-derived growth factor B, and may have therapeutic potential activity against meningiomas. bone morphogenetic proteins. PDGF and EGF play a critical For instance, inhibits EGFR and human epidermal role in the activation of main anti-apoptotic cell signaling 2, HKI-272 inhibits all subtypes of pathways [rat sarcoma (RAS)/mitogen-activated protein the EGFR, and ZD6474 inhibits EGFR and VEGFR. kinase (MAPK)] and phosphoinositide 3 kinase–protein Humanized monoclonal antibodies to EGFR, including kinase B (PI3K–AKT) and of a secondary pathway , , , EMD 72000, mAb phospholipase C-γ1-protein kinase C (45). Activating PI3K 806, and are being investigated (52-55). In a leads to AKT phosphorylation and p70 (S6K) activation by phase I study of a murine against way of mammalian target of rapamycin (mTOR). High levels EGFR in nine patients with either or meningioma, of phosphorylated AKT are found in atypical and anaplastic treatment was well tolerated, but no radiographic responses meningiomas. Inhibition of this pathway with selective were detected (56). mitogen activated protein kinase kinase 1 (MEK1) inhibitors VEGF and VEGFRs mediate angiogenesis in various types has shown reduced MAPK activity and inhibition in of brain tumors (57). VEGF is up-regulated in meningiomas meningioma cell cultures (45). Farnesyl transferase (58) even if, Barresi and Tuccari showed the absence of inhibitors, a class of chemotherapeutic agents that block correlation between VEGF expression and WHO tumor farnesyl transferase, thereby inhibiting RAS localization and grade (59). Additionally, VEGF plays an important role in activation to the cytoplasmic surface of the receptor are the formation of peritumoral edema, which adds to the under investigation (45). morbidity associated with these tumors. is a The invasiveness of neoplastic cells of human monoclonal antibody that binds VEGFB inhibiting meningiomas has been related to expression of matrix- angiogenesis. Inhibition of VEGF by bevacizumab also metalloproteinase-9, a peptidase actively implicated in the affects the tumor vasculature, suppressing new blood vessel degradation of the extracellular matrix (46). A plasmid vector growth and the existing vasculature (60). Underlying was used to transfect meningioma cells in vitro and in vivo mechanisms of angiogenesis inhibition include a direct with complementary double-stranded RNA to cathepsin B antitumor effect, endothelial cell radiosensitization resulting and matrix-metalloproteinase-9 mRNA. Decreased in damaged tumor vasculature, and improved oxygenation as expression of these enzymes, associated with a significant a result of elimination of tumor vessels and decrease in reduction of meningioma migration and invasiveness, was interstitial pressure (61). In a retrospective review by Lou et observed (47). Merlin is a member of the erzin- al., the utility of bevacizumab-based therapy for radixinmoesin family of proteins and interacts with the recurrent/progressive meningiomas was evaluated. They

6394 Caruso et al: Meningioma Treatment (Review) suggested that bevacizumab led to a response in recurrent analyzing expression in tissue microarrays of human meningioma (62). In a recent study about the use of meningiomas and in cell cultures, and subcutaneous and bevacizumab in patients with NF2, the authors disclosed the intracranial nude mouse models. The data showed that significant expression of SEMA3, an angiogenesis inhibitor, cilengitide is not likely to achieve major responses against and the absence of any correlation between expression of rapidly growing malignant meningiomas, although brain VEGF pathway components and tumor microvascular invasion may be reduced because of the strong antimigratory density. The same authors affirmed that the effects of properties of the drug. Its combination with radiotherapy bevacizumab on meningiomas were not clear and the relative deserved further attention (72). effect on response was small, and likely not clinically relevant (63). Additionally, there are currently several Tumor-suppressor proteins. A family of membrane-bound ongoing trials incorporating VEGF/VEGFR-directed therapy proteins known as the Band 4.1 family has been discovered for patients with recurrent, progressive meningioma, on the cytoplasmic side of the cell membrane (73). Genetic including a multicenter phase II trial combining bevacizumab mutations that lead to abnormal function of these proteins with the mTOR inhibitor everolimus, and separate phase II are believed to be one of the main causes for meningioma study evaluating bevacizumab as single agent development. Gutmann et al. showed that loss of protein (NCT00972335 and NCT01125046). 4.1B appears to be similarly distributed among meningioma PDGFB is another crucial factor that promotes the grades, again suggesting this to be an early event in the recruitment and proliferation of vascular cells. It can induce formation of meningiomas (74). Protein 4.1B was revealed the transcription and secretion of VEGF. PDGFB and to interact with the cell growth regulator protein 14-3-3. PDGFRB are expressed in meningiomas, and their Although aggressive meningiomas show reduced levels of overexpression correlates with the WHO grade (64). Pfister 14-3-3 expression, impaired 14-3-3 function has not been et al. recently tested the effects of gambogic acid and two shown to affect protein 4.1B function, suggesting that inhibitors of PDGFRB ( and alternative signaling pathways are present (5). tandutinib) on meningiomas in vitro, concluding that these Liu and colleagues studied the expression and role of PDGFRB inhibitors inhibit the migration of meningioma periostin in meningiomas (75). It seems that periostin and cells in vitro (65). Imatinib mesylate (Gleevec) is an inhibitor Ki-67 may play a role in predicting the grade and prognosis of PDGFRA and -B, FMS-related tyrosine kinase 1 (FLT1), of meningiomas. Drugs targeting periostin aim at reducing and tyrosine-proyein kinase (KIT). Two phase II trials have invasion of meningiomas (75). Recently, Zhang et al. been reported on the use of imatinib alone and in disclosed the existence of five genes [NF2, meningioma 1 combination with hydroxyurea, enrolling 23 and 21 patients, (MN1), AT rich interactive domain 1B (ARID1B), sema respectively. As a single-agent, imatinib was well-tolerated domain (SEMA4D), and mucin 5 (MUC5)] that carry novel but had no significant activity against recurrent protein-altering variations that can be associated with meningiomas. PFS at 6 months for patients with benign progression of meningioma. They also documented the meningiomas was 45%, and for those with atypical and candidate genes, NF2 and MN1 to be associated with malignant meningiomas, it was 0% (66, 67). A recent study malignant meningioma (75). Recently Burns et al. reported evaluated the efficacy of sunitinib in 36 patients with that in vitro AR-42, a pan-histone deacetylase inhibitor, malignant meningioma. The PFS rate was 42%, meeting the inhibited proliferation of both Ben-Men-1 and normal primary end-point of the study (68). Gupta et al. reported meningeal cells by increasing expression of p16 (INK4A), that nelfinavir, an anti-retroviral drug, can strengthen the p21(CIP1/WAF1), and p27(KIP1) (72). AR-42 reduced the efficacy of imatinib therapy (69). Similarly, Johnson et al. levels of cyclins D1, E and A, and proliferating cell nuclear described reduced meningioma growth in cell lines exposed antigen in meningeal cells while significantly reducing the to lopinavir, another antiretroviral drug (70). Second- expression of cyclin B, important for progression through the generation PDGF inhibitors such as or , G2 phase in Ben-Men-1 cells. The differential effect of AR- which are thought to be more potent inhibitors have not been 42 on cell-cycle progression of normal meningeal and tested on meningioma cells. meningioma cells may have therapeutic implications (76). In 2006, a study concerning transfection of tissue factor pathway inhibitor 2 (TFPI2) mRNA in the malignant Other Systemic Therapies meningioma cell line IOMM-Lee evaluated tumor growth in vitro and in vivo suggested that TFPI2 could have therapeutic Estrogen and progesterone receptor antagonists. Hormonal potential in malignant meningioma (71). Recently, Wilisch- therapies have received considerable interest following the Neumann et al. published a study concerning the impact of observation of the high incidence of meningioma in the cilengitide, an inhibitor of αvβ5 , on migration, women of reproductive age and the discovery that up to proliferation, and radiosensitization of meningioma cells, two-thirds of meningiomas express progesterone and

6395 ANTICANCER RESEARCH 35: 6391-6400 (2015) androgen receptors (4). In addition, several Interferon-α 2B (IFNα). IFNα is a leukocyte-produced epidemiological studies have suggested that administration cytokine that has been shown to inhibit meningioma cells in of estrogens and progestins affect women's risk of vitro. Very few studies were published that used IFNα for developing meningioma (77, 78). A phase II study recurrent meningioma showing a modest effect (89, 90). The including 19 patients with non-resectable refractory largest such study was published by Chamberlain and Glantz meningiomas showed no efficacy benefit of tamoxifen, an in 2008 (91). Thirty-five patients with recurrent estrogen receptor antagonist, in the inhibition of meningiomas were enrolled. Although the patients did not meningioma growth (79). These findings are possibly due demonstrate a significant partial or complete radiographic to the relatively infrequent estrogen receptor expression in response, IFNα had cytostatic activity, achieving meaningful meningioma. Because of the higher likelihood of palliation, as reflected by a 6-month PFS rate of 54%. progesterone receptor expression in meningiomas, several studies evaluated the role of progesterone receptor MicroRNA. MicroRNAs (miRNAs) are a group of short antagonists as possible candidate drugs. Initial studies of (from 21- to 23) nucleotides that control the expression of the anti-progesterone mifepristone (RU486) were many target genes at the post-transcriptional level. They are promising (80, 81). However, their findings were refuted aberrantly expressed in many types of cancer and play a by a large, prospective multi-center, randomized phase III major role in regulating a large number of pathways. clinical trial enrolling 180 patients which failed to show Therapeutic strategies can include direct tumor-suppressive any major benefit of mifepristone over placebo (82). These effects, anti-angiogenic effects, anti-metastatic effects, findings might be explained by the fact that this study suppression of immune evasion of tumors, and sensitization enrolled patients with meningioma subtypes characterized of tumor cells to classical anticancer treatments. Recent data by reduced expression of progesterone receptors. A recent suggest that the use of miRNA profiling has significant trial evaluating mifepristone in a pre-selected population potential as an effective diagnostic and prognostic tool in with diffuse meningiomatosis highly expressing defining the expression signature of meningiomas. Down- progesterone receptor demonstrated a significant long- regulation of miR-29c-3p and miR-219-5p were found to be lasting clinical and radiological response or stabilization associated with advanced clinical stages of meningioma. In (83). Taken together, these studies suggest that potential addition, these data showed that high expression of miR- sub-groups of patients with meningioma are more likely to 190a and low expression of miR-29c-3p and miR-219-5p benefit from mifepristone and support its use in further correlated significantly with higher recurrence rates in prospective clinical trials of preselected populations. patients with meningioma (92). A recent research study demonstrated a valid antimigratory and antiproliferative Somatostatin receptor agonists. Somatostatins (SSTs) are a function of miR-145 against meningiomas (93). family of neuropeptides produced in the hypothalamus Overexpression of miR-145 in IOMM-Lee meningioma cells involved in a wide range of physiological processes, resulted in reduced proliferation, increased sensitivity to including neuromodulation and inhibition of secretory apoptosis, and reduction of orthotopic tumor growth in nude processes and cell proliferation (84). Meningiomas are mice. Moreover, meningioma cells with high miR-145 levels known to have a high frequency of somatostatin receptor had impaired migratory and invasive potential both in vitro expression (up to 90%), especially of the SST2A sub-type, and in vivo (94). A novel experimental study has although their functional role remains unclear. Experimental demonstrated a key role for miR-200a down-regulation in and human studies have evaluated the effect of somatostatin promoting the growth of meningiomas. Reduced levels of and somatostatin analogs on meningioma growth, with miR-200a appear to contribute to tumorigenesis through two contradictory results (85, 86). A prospective pilot trial of a pathways mediated by up-regulation of three mRNA targets long-acting somatostatin analog agonist (Sandostatin LAR®) (94). Recent data confirmed that elevated levels of miR-335 reported a partial radiographic response in 31% of patients increased cell growth and inhibited cell cycle arrest in the with recurrent meningiomas and the PFS at 6 months was G0/G1 phase in vitro. It is probably that miR-335 plays an 44% (87). Pasireotide (SOM230), a novel long-acting essential role in the proliferation of meningioma cells by somatostatin analog, has a wider somatostatin receptor directly targeting the retinoblastoma gene 1 (Rb1) signaling spectrum (including sub-types 1, 2, 3, and 5) and has a pathway (95). higher affinity than octreotide. A recently completed randomized phase II clinical trial was designed to evaluate Conclusion whether pasireotide LAR (SOM230C) prolongs PFS at 6 months in patients with recurrent or progressive meningioma. The majority of meningiomas are benign with a low risk of The study demonstrated that it has limited activity against recurrence following surgical resection. On the other hand, recurrent meningioma (88). grade II and III meningiomas have a higher rate of

6396 Caruso et al: Meningioma Treatment (Review) recurrence, despite complete removal with surgery. In collagen in secretory meningiomas. J Clin Neurosci 15(7): 806- addition, there is a small subset of patients with grade I 811, 2008. tumors which progress to high-grade pathology when they 8 Stafford SL, Perry A, Suman VJ, Meyer FB, Scheithauer BW, recur. Initial treatment for symptomatic meningiomas Lohse CM and Shaw EG: Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, commonly involves surgical resection which may be 1978 through 1988. Mayo Clin Proc 73(10): 936-942, 1998. followed by either external beam radiation therapy or 9 Simpson D: The recurrence of intracranial meningiomas after stereotactic radiosurgery. However, despite advances in surgical treatment. J Neurol Neurosurg Psychiatry 20(1): 22-39, surgery, radiation therapy and radiosurgery, there remains a 1957. small subset of patients with meningiomas in whom the 10 Kinjo T, al-Mefty O and Kanaan I: Grade zero removal of disease recurs and in whom the recurrent tumors are supratentorial convexity meningiomas. Neurosurgery 33(3): 394- refractory to conventional therapies. Progress in identifying 399, 1993. 11 Borovich B and Doron Y: Recurrence of intracranial effective therapies for these kind of meningioma has been meningiomas: the role played by regional multicentricity. J limited by the lack of cell lines and adequate animal models Neurosurg 64(1): 58-63, 1986. for experimental studies, the heterogeneity of patient 12 Kamitani H, Masuzawa H, Kanazawa I and Kubo T: Recurrence populations, and lack of objective response criteria for of convexity meningiomas: tumor cells in the arachnoid evaluating treatment. Of particular interest are combination membrane. Surg Neurol 56(4): 228-235, 2001. therapies that affect multiple pathways and nanomedicine, 13 Bie L, Zhao G, Ju Y, Zhang B: Integrative genomic analysis which has the advantage of being able to target multiple identifies CCNB1 and CDC2 as candidate genes associated 204 tumor markers and deliver multiple agents simultaneously with meningioma recurrence. Cancer Genet : 536-540, 2011. addressing the challenges of cancer heterogeneity and 14 Perez-Magan E, Rodrıguez de Lope A, Ribalta T, Ruano Y, adaptive resistance at once. In this field, the development of Campos-Martin Y, Perz-Bautista G: Differential expression selective drug-delivery systems to direct the diffusion of profiling analyses identifies down-regulation of 1p, 6q and 14q drugs, engineered monoclonal antibodies, and other genes and overexpression of 6p histone cluster 1 genes as therapeutic molecules into the CNS is very important. markers of recurrence in meningiomas. 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