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.^43–47 Most meningiomas of all histologic grades express PDGF ligands AA and BB and the PDGF-beta receptor (PDGF-βR).^43–47 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.^55–61 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