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Matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin (MMP-9/NGAL) complex activity is elevated in brain tumors and may serve as a molecular marker for brain tumors. However, the relationship between MMP-9/NGAL activity in brain tumors and patient prognosis and treatment response remains unclear. Here, we compared the clinical characteristics of glioma patients with the MMP-9/NGAL activity measured in their respective tumor and urine samples. Using gelatin zymography assays, we found that MMP-9/NGAL activity was significantly increased in tumor tissues (TT) and preoperative urine samples (Preop-1d urine). Activity was reduced by seven days after surgery (Postop-1w urine) and elevated again in cases of tumor recurrence. The MMP-9/NGAL status correlated well with MRI-based tumor assessments. These findings suggest that MMP-9/NGAL activity could be a novel marker to detect gliomas and predict the clinical outcome of patients.

Background: In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies., Methods: Eligible patients had CNS malignancies that required a (minimum) 2-week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3., Results: Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8-3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤ 2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow-up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6-month progression-free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT., Conclusions: Continuous 37.5-mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial., (Copyright © 2011 American Cancer Society.)

Purpose: A major difficulty in treating brain tumors is the lack of effective methods of identifying novel or recurrent disease. In this study, we have evaluated the efficacy of urinary matrix metalloproteinases (MMP) as diagnostic biomarkers for brain tumors., Experimental Design: Urine, cerebrospinal fluid, and tissue specimens were collected from patients with brain tumors. Zymography, ELISA, and immunohistochemistry were used to characterize the presence of MMP-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL), and vascular endothelial growth factor (VEGF). Results were compared between age- and sex-matched controls and subjected to univariate and multivariate statistical analyses., Results: Evaluation of a specific panel of urinary biomarkers by ELISA showed significant elevations of MMP-2, MMP-9, MMP-9/NGAL, and VEGF (all P < 0.001) in samples from brain tumor patients compared with controls. Multiplexing MMP-2 and VEGF provided superior accuracy compared with any other combination or individual biomarker. Receiver-operating characteristics curves for MMP-2 and VEGF showed excellent discrimination. Immunohistochemistry identified these same proteins in the source tumor tissue. A subset of patients with longitudinal follow-up revealed subsequent clearing of biomarkers after tumor resection., Conclusion: We report, for the first time, the identification of a panel of urinary biomarkers that predicts the presence of brain tumors. These biomarkers correlate with presence of disease, decrease with treatment, and can be tracked from source tissue to urine. These data support the hypothesis that urinary MMPs and associated proteins are useful predictors of the presence of brain tumors and may provide a basis for a novel, noninvasive method to identify new brain tumors and monitor known tumors after treatment.