Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor

Norden-Zfoni, A., Desai, J., Manola, J., Beaudry, P., Force, J., Maki, R., Folkman, J., Bello, C., Baum, C., DePrimo, S. E., Shalinsky, D. R., Demetri, G. D., Heymach, J. V. (May 2007) Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer Res, 13 (9). pp. 2643-50. ISSN 1078-0432 (Print)1078-0432 (Linking)

DOI: 10.1158/1078-0432.CCR-06-0919


PURPOSE: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors. EXPERIMENTAL DESIGN: Patients (n=73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of >6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC). RESULTS: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus -0.01 CEC/microL/d, P=0.03) and smaller decreases in monocyte levels (47% versus 60%, P=0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment. CONCLUSIONS: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.

Item Type: Paper
Uncontrolled Keywords: Adult Antineoplastic Agents/*therapeutic use Benzamides Biomarkers/blood Endothelial Cells Female Gastrointestinal Stromal Tumors/*blood/*drug therapy Humans Imatinib Mesylate Indoles/*therapeutic use Male Monocytes Piperazines/therapeutic use Pyrimidines/therapeutic use Pyrroles/*therapeutic use Treatment Outcome Vascular Endothelial Growth Factor A/*blood Vascular Endothelial Growth Factor Receptor-2/*blood
Subjects: diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > gastrointestinal stromal tumors
diseases & disorders > cancer > metastasis
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: 1 May 2007
Date Deposited: 26 Oct 2016 19:37
Last Modified: 26 Oct 2016 19:37
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