title: 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-1alpha, IP-10, cutaneous T-cell-attracting chemokine, monokine induced by IFN-gamma, tumor necrosis factor-related apoptosis-inducing ligand, and IFN-alpha. 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.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Petros G
authors.initials: PG
authors.lastname: Nikolinakos
authors.forename: Nasser
authors.initials: N
authors.lastname: Altorki
authors.forename: David
authors.initials: D
authors.lastname: Yankelevitz
authors.forename: Hai T
authors.initials: HT
authors.lastname: Tran
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Yan
authors.forename: Dilip
authors.initials: D
authors.lastname: Rajagopalan
authors.forename: Walter
authors.initials: W
authors.lastname: Bordogna
authors.forename: Lone H
authors.initials: LH
authors.lastname: Ottesen
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
mesh_terms: D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000097:blood*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D016000:Cluster Analysis; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D007191:Indazoles; D008175:Lung Neoplasms / Q000097:blood* / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D011743:Pyrimidines / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D016207:Cytokines; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib