Plasma Cytokine and Angiogenic Factor Profiling Identifies Markers Associated with Tumor Shrinkage in Early-Stage Non–Small Cell Lung Cancer Patients Treated with Pazopanib
- 14 March 2010
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (6), 2171-2179
- https://doi.org/10.1158/0008-5472.can-09-2533
Abstract
There is an unmet need for pharmacodynamic and predictive biomarkers for antiangiogenic agents. Recent studies have shown that soluble vascular endothelial growth factor receptor 2 (sVEGFR2), VEGF, and several other soluble factors may be modulated by VEGF pathway inhibitors. We conducted a broad profiling of cytokine and angiogenic factors (CAF) to investigate the relationship between baseline CAF levels, CAF changes during treatment, and tumor shrinkage in early-stage non–small cell lung cancer (NSCLC) patients treated with pazopanib, an oral angiogenesis inhibitor targeting VEGFR, platelet-derived growth factor receptor, and c-kit. Plasma samples were collected before treatment and on the last day of therapy from 33 patients with early-stage NSCLC participating in a single-arm phase II trial. Levels of 31 CAFs were measured by suspension bead multiplex assays or ELISA and correlated with change in tumor volume. Pazopanib therapy was associated with significant changes of eight CAFs; sVEGFR2 showed the largest decrease, whereas placental growth factor underwent the largest increase. Increases were also observed in stromal cell–derived factor-1α, IP-10, cutaneous T-cell–attracting chemokine, monokine induced by IFN-γ, tumor necrosis factor–related apoptosis-inducing ligand, and IFN-α. Posttreatment changes in plasma sVEGFR2 and interleukin (IL)-4 significantly correlated with tumor shrinkage. Baseline levels of 11 CAFs significantly correlated with tumor shrinkage, with IL-12 showing the strongest association. Using multivariate classification, a baseline CAF signature consisting of hepatocyte growth factor and IL-12 was associated with tumor response to pazopanib and identified responding patients with 81% accuracy. These data suggest that CAF profiling may be useful for identifying patients likely to benefit from pazopanib, and merit further investigation in clinical trials. Cancer Res; 70(6); 2171–9Keywords
This publication has 47 references indexed in Scilit:
- Evaluating Variability in Tumor Measurements from Same-day Repeat CT Scans of Patients with Non–Small Cell Lung CancerRadiology, 2009
- VEGF-A Stimulates ADAM17-Dependent Shedding of VEGFR2 and Crosstalk Between VEGFR2 and ERK SignalingCirculation Research, 2008
- Modes of resistance to anti-angiogenic therapyNature Reviews Cancer, 2008
- Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacyProceedings of the National Academy of Sciences of the United States of America, 2007
- Molecular and cellular biomarkers for angiogenesis in clinical oncologyDrug Discovery Today, 2007
- AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma PatientsCancer Cell, 2007
- Effect of interleukin-4 on vascular endothelial growth factor production in rheumatoid synovial fibroblastsClinical and Experimental Immunology, 2006
- Scatter-factor and semaphorin receptors: cell signalling for invasive growthNature Reviews Cancer, 2002
- Patterns and Emerging Mechanisms of the Angiogenic Switch during TumorigenesisCell, 1996
- What Is the Evidence That Tumors Are Angiogenesis Dependent?JNCI Journal of the National Cancer Institute, 1990