Chemotherapy and Experimental Medical Therapies for Meningiomas

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CHAPTER 56 Chemotherapy and Experimental Medical Therapies for Meningiomas

INTRODUCTION

Current therapies for meningiomas include surgery, radiation therapy and stereotactic radiosurgery.19 For the majority of patients with benign meningiomas (World Health Organization [WHO] grade I) and a subset of patients with atypical meningiomas (WHO grade II), these therapies are effective in achieving tumor control. However, there is an important group of patients with inoperable or higher grade tumors who develop recurrent disease after surgery and radiation therapy. The treatment options for these patients are currently inadequate.

The WHO classification scheme for meningiomas is based on the degree of anaplasia, number of mitoses, and presence of necrosis.10 Histological grading is important because it helps to predict the likelihood of recurrence. Benign meningiomas account for more than 90% of tumors and have a low risk of recurrence (7%–20%).1012 Atypical meningiomas are much less common. They account for 4.7% to 7.2% of meningiomas and are associated with a 40% recurrence rate despite surgical resection.12 Malignant meningiomas represent only 1% to 2.8% of meningiomas but recur in 50% to 80% of cases and usually result in death within 2 years of diagnosis.10,11 Patients with meningiomas of any histological grade that recur after surgery and radiation therapy are frequently considered for chemotherapy or experimental medical therapies.

CYTOTOXIC CHEMOTHERAPY

To date, chemotherapy has had only a very limited role in the treatment of meningiomas. Data from small clinical trials and case series suggest that most chemotherapeutic agents have minimal activity against meningiomas.5,6,13,14 The evaluation of chemotherapy has also been complicated by the lack of data regarding the natural history of untreated meningiomas. Many chemotherapy studies report variable periods of disease stabilization, but it is difficult to know whether this represents an improvement because benign meningiomas grow slowly and may appear radiographically stable for prolonged periods.15,16

In general, chemotherapeutic regimens (such as dacarbazine and Adriamycin) that have activity in other soft tissue tumors have produced disappointing results in patients with meningiomas.6 Hydroxyurea, an oral ribonucleotide reductase inhibitor, arrests meningioma cell growth in the S phase of the cell cycle and induces apoptosis.17 In a preliminary report, hydroxyurea (1000–1500 mg/day; 20 mg/kg/day) decreased tumor size in three patients with recurrent benign meningiomas and prevented recurrent disease for 24 months in a patient with a completely resected malignant meningioma.18 Several more recent studies suggest that hydroxyurea has modest activity; responses are uncommon but some patients appear to have disease stabilization.1923 The Southwest Oncology Group conducted a phase II study to further evaluate the role of hydroxyurea in meningiomas (SWOG-S9811). This study is closed to accrual but the final results are not yet available.

There have been reports of small numbers of patients with malignant meningiomas who responded to recombinant interferon alpha-2b.24,25 Temozolomide (Temodar, TMZ), an alkylating agent with activity in malignant gliomas, was evaluated in 16 patients with refractory meningiomas and showed negligible activity.26 The topoisomerase inhibitor irinotecan (Camptosar, CPT-11) caused moderate toxicity in 16 patients with benign meningiomas and had no demonstrable activity.27 A large number of cytotoxic agents are under evaluation for sarcomas and other systemic malignancies.28 Most of these have not been evaluated in meningiomas, and it is possible that some may have modest activity. However, it is likely that the more novel therapeutic approaches discussed in the text that follows will provide a greater chance of improving the outcome for patients with recurrent meningiomas.

CHALLENGES IN THE DEVELOPMENT OF EFFECTIVE MEDICAL THERAPIES FOR MENINGIOMAS

In contrast to the extensive understanding of the molecular pathogenesis and biology of systemic malignancies, and even brain tumors such as malignant gliomas, relatively little is known about the molecular pathogenesis of meningiomas and the critical molecular changes driving tumor growth.11,12,29,30 Overexpression of various growth factors including platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) and their receptors, and signal transduction pathways such as the Ras/mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K)-Akt, and phospholipase C (PLC)-γ1-protein kinase C (PKC) pathways have been implicated, but their relative significance is largely unknown.29,30 As a result, the most important molecular targets may remain to be elucidated.

Another factor limiting progress in the development of more effective therapies for meningiomas is the lack of robust cell lines and animal models. There is a need for animal models that replicate the genetic changes in meningiomas with a high frequency of spontaneous meningioma development, benign meningioma lines for in vitro and in vivo studies, and meningeal specific promoters. Many of the existing meningioma cell lines are derived from malignant meningiomas and likely contain culture-induced artifacts and lack progesterone receptors.12 There are some orthotopic31,32 and genetic models33 in development that appear promising. Recently, two cell lines were developed from benign meningioma specimens via immortalization with human telomerase reverse transcriptase and SV40 large T antigen. Orthotopic tumors with similar immunostaining patterns to human meningiomas were established from both cell lines in athymic nude mice.31 Another model uses a Cre recombinase technology to inactivate NF2 in arachnoid cells, resulting in intracranial meningothelial hyperplasia and meningiomas in 30% of mice.33 These models may aid in the preclinical evaluation of novel therapies.

The lack of data regarding the natural history of untreated meningiomas is another important limiting factor that impedes progress. Without such data, it is difficult to know if the periods of disease stabilization reported in various studies represent an improvement over no therapy.

A final factor limiting progress is the relatively small number of patients with meningiomas who require additional therapies after treatment with surgery and radiation therapy. In general, there is little incentive for pharmaceutical companies to evaluate their therapies in meningiomas because of the small potential market. Hopefully as the molecular pathogenesis of these tumors becomes better understood, a compelling case can be made for evaluating specific agents directed at critical molecular targets. In the next section, targeted molecular drugs that have a potential role against meningiomas are reviewed in detail. These therapies have also been discussed in recent review articles.2,5,30,34

EXPERIMENTAL THERAPIES: TARGETED MOLECULAR AGENTS

Recently, it has become apparent that many human diseases result from aberrations in cell signaling pathways. Protein-tyrosine kinases play a fundamental role in signal transduction, and deregulated activity of these enzymes has been observed in many cancers. Therefore, specific inhibitors of tyrosine kinases could have potential therapeutic applications in the treatment of cancer, with potentially lower toxicity and/or higher, prolonged response rates.35,36 The prototypical targeted molecular agent is imatinib mesylate (Gleevec), which has shown significant benefit in chronic myeloid leukemia (CML)37 and gastrointestinal stromal tumors (GIST).38 There is also a growing experience with targeted molecular agents in malignant gliomas.3941 However, to date, there have been minimal data on the use of these agents in meningiomas.

In contrast to the extensive work aimed at understanding the genetics of meningiomas, relatively little work has been conducted to understand the growth factors and their receptors, and the signal transduction pathways that are critical to meningioma growth.2,5,30 PDGF, EGF, VEGF, insulin-like growth factor (IGF), transforming growth factor-beta (TGF-β), and their receptor tyrosine kinases, together with their downstream signaling pathways including the Ras/MAPK pathway, the PI3K/Akt pathway, the PLC-γ1-PKC pathway, and the TGF-β-SMAD pathways, are all thought to be important in meningioma growth (Fig. 56-1).30

Platelet-Derived Growth Factor Receptor

PDGF is a fundamental driver of cell proliferation in normal development and in a variety of pathological conditions, including cancer.42 Accumulating evidence suggests that PDGF plays an important role in meningioma growth.4347 Most meningiomas of all histologic grades express PDGF ligands AA and BB and the PDGF-beta receptor (PDGF-βR).4347 Expression levels may be higher in atypical and malignant meningiomas than in benign meningiomas.45 Laboratory data suggest that an autocrine PDGF loop supports meningioma cell growth and maintenance.47 When PDGF-BB is applied to cultured meningioma cells, MAPK48 and c-fos49 are activated and tumor cell proliferation is enhanced. Conversely, anti-PDGF-BB antibodies inhibit cell growth.50 These data provide sound rationale for testing PDGF inhibitors in meningioma patients.

Imatinib is a potent inhibitor of the Bcr-Abl, PDGF-α and β receptors, and c-Kit tyrosine kinases.51 Its ability to inhibit PDGFR with an IC50 of 0.1 μM suggested that it may have therapeutic potential in meningiomas. The North American Brain Tumor Consortium (NABTC) conducted a phase II study of imatinib in patients with recurrent meningiomas (NABTC 01-08).52 Patients were stratified into two cohorts: (1) benign meningiomas or (2) atypical and malignant meningiomas. As imatinib is metabolized by the cytochrome P450 system (3A4), patients could not be receiving enzyme inducing antiepileptic drugs (EIAEDs). Patients initially received 600 mg/day of imatinib; the dose was increased in the second cycle to 800 mg/day if no significant toxicity was observed in the first cycle. Twenty-three patients were enrolled into the study (13 with meningiomas, 5 with atypical meningiomas, and 5 with malignant meningiomas). Though the treatment was generally well tolerated, imatinib had minimal activity. Of the 19 patients evaluable for response, 10 progressed at the first scan and 9 were stable. There were no radiographic responses. Overall median progression-free survival (PFS) was 2 months (range 0.7 to 18 months); 6-month PFS was 29.4%. For benign meningiomas, median PFS was 3 months; 6-month PFS was 45%. For the atypical and malignant meningiomas, median PFS was 2 months; 6-month PFS was 0%. Several other inhibitors of PDGF are undergoing evaluation such as sunitinib, MLN518, dasatinib, AMN 107, pazopanib, CP673451 and CHIR 265. Some of these, such as MLN518, are more potent PDGFR inhibitors than imatinib, whereas others target additional kinases that are potentially important in meningiomas. For example, pazopanib also inhibits VEGF receptors (VEGFR) 1, 2, and 3 as well as c-Kit, while CHIR 265 inhibits VEGFR, c-Kit and Raf. These drugs may be more effective than imatinib as monotherapy against meningiomas.

There is also interest in combining imatinib with hydroxyurea, the cytotoxic chemotherapy agent with the most activity in meningiomas. Though a recent phase I/II trial of imatinib as monotherapy for recurrent malignant glioma showed minimal activity,53 a study of 33 recurrent glioblastoma (GBM) patients treated with the combination of imatinib mesylate (400 mg/day or 500 mg twice/day, depending on concurrent EIAED use) and hydroxyurea (500 mg twice/day), had encouraging results.54 After a median follow-up period of 58 weeks, 1 patient achieved a complete response, 2 achieved a partial response, and 14 achieved stable disease. Six-month PFS was 27%, and the median PFS was 14.4 weeks. In light of these results in patients with recurrent GBM, a multicenter phase II trial of the combination for patients with recurrent or progressive meningiomas after surgery is currently in progress (ClinicalTrials.gov identifier NCT00354913). Twenty-one patients are expected to enroll, and monitoring includes magnetic resonance imaging (MRI) scans and clinical examinations every 8 weeks.

Epidermal Growth Factor Receptor

The EGFR is overexpressed in more than 60% of meningiomas.5561 EGF and TGF-β activate these receptors and stimulate meningioma growth in vitro,30,56 supporting the concept that activation of EGFRs in human meningiomas by autocrine/paracrine stimulation may contribute to their proliferation. Increased TGF-β immunoreactivity in meningiomas has been associated with aggressive growth.30,61,62

The NABTC conducted two trials of EGFR inhibitors in meningiomas. In NABTC 01-03 patients with recurrent or progressive meningiomas not receiving EIAEDs were treated with 150 mg/day of erlotinib (Tarceva). In NABTC 00-01, patients with recurrent or progressive meningiomas not on EIAEDs were treated with 500 mg/day of gefitinib (Iressa). In both studies, the drugs were reasonably well tolerated; the main toxicities were the expected adverse effects of rash and diarrhea. Both studies have closed to accrual, but the final results are not yet available.

In addition to gefitinib and erlotinib, there are a large number of other agents currently undergoing evaluation. These inhibit EGFR alone, or together with other receptor tyrosine kinases, which may have therapeutic potential in meningiomas (Table 56-1). For example, lapatinib inhibits EGFR and HER2, HKI-272 inhibits all subtypes of the EGFR, and ZD6474 (Zactima) inhibits EGFR and VEGFR. Although EGFR monoclonal antibodies have been effective for some systemic malignancies (e.g., cetuximab in colorectal cancer), they have generally not been used for brain tumors because of the concern regarding the ability of these agents to pass through the blood–brain barrier (BBB) in sufficient concentrations to produce a therapeutic effect. Because the BBB is not a factor in most meningiomas, it is possible that these antibodies may be effective in these tumors. To date very few studies have evaluated the therapeutic potential of these agents in meningiomas. In a phase I study of a murine monoclonal antibody against EGFR in nine patients with either gliomas or meningiomas, treatment was reasonably well tolerated. No radiographic responses were detected, but efficacy data is difficult to interpret in a study with so few subjects.63 Currently, several anti-EGFR antibodies are undergoing evaluation for other malignancies such as cetuximab, panitumumab, EMD 72000, nimotuzumab, and mAb 806. Trials of these agents in meningiomas may be worthwhile, especially if combined with correlative studies examining whether the antibodies can achieve therapeutic concentrations in meningiomas and inhibit EGFR in vivo.

TABLE 56-1 Selected potential targeted molecular drugs for meningiomas

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Class/agent Alternative name(s) Mechanism(s)
Apoptosis enhancers    
ABT737   Bcl-2 inhibitor
AT101   Bcl-2 inhibitor
Fenretinide   Multiple targets
GX15-070   Bcl-2 inhibitor
Integrin inhibitor    
Cilengitide   αvβ3 and αvβ5 integrin inhibitor
Cell cycle inhibitors    
AG024322   pan-CDK inhibitor
AZ703   CDK 2, 1 inhibitor
BMS-387032   CDK 2, 1 inhibitor
CINK4   CDK 4, 6 inhibitor
E7070   Unknown
Flavopiridol   pan-CDK inhibitor
PD-0332991   CDK 4, 6 inhibitor
Seliciclib   CDK 2, 1 inhibitor
c-MET (HGF/SF) inhibitors    
AMG-102   HGF/SF antibody
XL880   c-MET, VEGFR2, PDGFR, c-Kit, Tie-2 inhibitor
EGFR inhibitors    
AEE788   EGFR, VEGFR inhibitor
BIBW 2992   EGFR, HER2 inhibitor
Cetuximab Erbitux EGFR antibody
EMD 72000   EGFR antibody
Erlotinib OSI-774, Tarceva EGFR inhibitor
Gefitinib ZD1839, Iressa EGFR inhibitor
HKI-272   pan-EGFR inhibitor
Lapatinib GW-572016 EGFR, HER2 inhibitor
mAb 806   EGFR antibody
Nimotuzumab TheraCIM EGFR antibody
Panitumumab Vectibix EGFR antibody
ZD6474 Zactima EGFR, VEGFR inhibitor
Endothelin-A inhibitors    
Astrasentan Xinlay ETA inhibitor
ZD4054   ETA inhibitor
Farnesyltransferase inhibitors    
Lonafarnib SCH 66336, Sarasar FT inhibitor
Tipifarnib R115777, Zarnestra FT inhibitor
Histone deacetylase inhibitors    
Depsipeptide   HDAC inhibitor
Voronistat Suberoylanilide hydroxamic acid (SAHA) HDAC inhibitor
Valproic acid   HDAC inhibitor
HSP-90 inhibitors    
17AAG   HSP-90 inhibitor
17DMAG   HSP-90 inhibitor
IPI504   HSP-90 inhibitor
MEK inhibitors    
AZD6244   MEK inhibitor
PD0325901   MEK inhibitor
mTOR inhibitors    
AP23573   mTOR inhibitor
Everolimus RAD001 mTOR inhibitor
Rapamycin   mTOR inhibitor
Temsirolimis CCI-779, Torisel mTOR inhibitor
PDGFR inhibitors    
AMN 107   PDGFR, c-Kit, Bcr-Abl inhibitor
CHIR 265   PDGFR, Raf, VEGFR, c-Kit inhibitor
CP-673-451    
Dasatinib   PDGFR, Src, c-Kit, ephrin A inhibitor
Imatinib mesylate Gleevec  
MLN518   PDGFR, c-Kit inhibitor
Pazopanib GW786034 PDGFR, VEGFR, c-Kit inhibitor
Sunitinib Sutent PDGFR, VEGFR, c-Kit inhibitor
Vatalanib PTK787 PDGFR, VEGFR inhibitor
XL-999   PDGFR, VEGFR, FGFR inhibitor
PKC β2 inhibitor    
Enzastaurin LY31761 PKC β2 inhibitor
PI3K inhibitor    
BEZ235   PI3K inhibitor
Proteasome inhibitor    
Bortezomib Velcade Proteasome inhibitor
Raf kinase inhibitor    
Sorafenib Nexavar, BAY 43-9006 Raf kinase, VEGFR, PDGFR inhibitor
Src inhibitor    
AZD0530   Src inhibitor
TGF-β inhibitors    
AP 12009   TGF-β2 antisense oligonucleotide
GC1008   TGF-β antibody
SB-431542   TGF-β receptor inhibitor
VEGF inhibitors    
Bevacizumab Avastin VEGF antibody
VEGF trap   VEGF soluble decoy receptor
VEGFR inhibitors    
AEE788   VEGFR, EGFR inhibitor
AG013736   VEGFR inhibitor
AMG 706   VEGFR inhibitor
AZD2171   VEGFR inhibitor
CEP-7055   VEGFR inhibitor
CHIR 265