Plasma Cytokine and Angiogenic Factor Profiling Identifies Markers Associated with Tumor Shrinkage in Early-Stage Non–Small Cell Lung Cancer Patients Treated with Pazopanib

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.

IL-12-dependent innate immunity arrests endothelial cells in G0–G1 phase by a p21Cip1/Waf1-mediated mechanism

“…However recent data may allow reconsidering this cytokine as a therapeutic tool in selected tumor subsets. Actually it has been reported that the in vivo tumor response to IL-12 is influenced by the molecular features of its receptor [63] and that IL-12 could be a candidate for tumor shrinkage observed during the treatment of early-stage non-small cell lung cancer with tyrosine kinase inhibitors (vandetanib, pazopanib) targeting angiogenic receptors [64,65]. …”

Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

“…In the last few years, knowledge about molecular mechanisms and cellular transformation in association with cancer behavior has increased [17][18][19] . More interest has been generated since the development of specific targeted therapies against the processes involved in the carcinogenesis of many types of cancers [20][21][22] .…”

Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

“…Other report using pre-clinical studies suggested that VEGF-A www.intechopen.com induced removal or shedding of VEGFR-2 in EC. VEGFR-2 shedding resulted in tumor shrinkage in NSCLC patients that was associated with expression of ADAM metalloprotease and IL-4 (Nikolinakos et al 2010). Taken together, these results suggest that VEGFR-2 is not only a mediator of angiogenesis but a viable target.…”

“…This supports the theory that anti-cancer drugs targeting the VEGF pathway are possible therapeutic means. The VEGF pathway has also recently been identified as a viable therapeutic target in NSCLC (Nikolinakos et al 2010). A study utilizing a mouse model to determine if initiation and maintenance of tumor angiogenesis in NSCLC could be associated with endothelial progenitor cells (EPCs CD133+) it was found these cells express high levels of VEGFR-2.…”