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

被引:94
作者
Nikolinakos, Petros G. [1 ]
Altorki, Nasser [3 ]
Yankelevitz, David [3 ]
Tran, Hai T.
Yan, Shaoyu
Rajagopalan, Dilip [4 ]
Bordogna, Walter [4 ]
Ottesen, Lone H. [4 ]
Heymach, John V. [2 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Unit 432, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA
[3] Cornell Univ, Joan & Sanford I Weill Med Coll, New York, NY 10021 USA
[4] GlaxoSmithKline, London, England
关键词
VASCULAR ENDOTHELIAL GROWTH; TYROSINE KINASE INHIBITOR; ADVANCED SOLID TUMORS; RANDOMIZED PHASE-II; COLORECTAL-CANCER; BIOMARKERS; VEGF; BEVACIZUMAB; TRIAL; CHEMOTHERAPY;
D O I
10.1158/0008-5472.CAN-09-2533
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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-1 alpha, 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. Cancer Res; 70(6); 2171-9. (C) 2010 AACR.
引用
收藏
页码:2171 / 2179
页数:9
相关论文
共 47 条
[1]   Nuclear factor-κB-related serum factors as longitudinal biomarkers of response and survival in advanced oropharyngeal carcinoma [J].
Allen, Clint ;
Duffy, Sonia ;
Teknos, Theodoros ;
Islam, Mozaffarul ;
Chen, Zhong ;
Albert, Paul S. ;
Wolf, Gregory ;
Van Wales, Carter .
CLINICAL CANCER RESEARCH, 2007, 13 (11) :3182-3190
[2]   Preoperative treatment with pazopanib (GW786034), a multikinase angiogenesis inhibitor in early-stage non-small cell lung cancer (NSCLC): A proof-of-concept phase II study [J].
Altorki, N. ;
Guarino, M. ;
Lee, P. ;
Pass, H. I. ;
Filip, E. ;
Bauer, T. ;
Roychowdhury, D. ;
Zaks, T. ;
Ottesen, L. ;
Yankelevitz, D. .
JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (15)
[3]  
Altorki N, 2008, ANN ONCOL, V19, P89
[4]   AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients [J].
Batchelor, Tracy T. ;
Sorensen, A. Gregory ;
di Tomaso, Emmanuelle ;
Zhang, Wei-Ting ;
Duda, Dan G. ;
Cohen, Kenneth S. ;
Kozak, Kevin R. ;
Cahill, Daniel P. ;
Chen, Poe-Jou ;
Zhu, Mingwang ;
Ancukiewicz, Marek ;
Mrugala, Maciej M. ;
Plotkin, Scott ;
Drappatz, Jan ;
Louis, David N. ;
Ivy, Percy ;
Scadden, David T. ;
Benner, Thomas ;
Loeffler, Jay S. ;
Wen, Patrick Y. ;
Jain, Rakesh K. .
CANCER CELL, 2007, 11 (01) :83-95
[5]   Modes of resistance to anti-angiogenic therapy [J].
Bergers, Gabriele ;
Hanahan, Douglas .
NATURE REVIEWS CANCER, 2008, 8 (08) :592-603
[6]   Molecular and cellular biomarkers for angiogenesis in clinical oncology [J].
Bertolini, Francesco ;
Mancuso, Patrizia ;
Shaked, Yuval ;
Kerbel, Robert S. .
DRUG DISCOVERY TODAY, 2007, 12 (19-20) :806-812
[7]   Phase II, Multicenter, Uncontrolled Trial of Single-Agent Sorafenib in Patients With Relapsed or Refractory, Advanced Non-Small-Cell Lung Cancer [J].
Blumenschein, George R., Jr. ;
Gatzemeier, Ulrich ;
Fossella, Frank ;
Stewart, David J. ;
Cupit, Lisa ;
Cihon, Frank ;
O'Leary, James ;
Reck, Martin .
JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (26) :4274-4280
[8]   VEGF as a Marker for Outcome Among Advanced Breast Cancer Patients Receiving anti-VEGF Therapy with Bevacizumab and Vinorelbine Chemotherapy [J].
Burstein, Harold J. ;
Chen, Yu-Hui ;
Parker, Leroy M. ;
Savoie, Jennifer ;
Younger, Jerry ;
Kuter, Irene ;
Ryan, Paula D. ;
Garber, Judy E. ;
Chen, Helen ;
Campos, Susana M. ;
Shulman, Lawrence N. ;
Harris, Lyndsay N. ;
Gelman, Rebecca ;
Winer, Eric P. .
CLINICAL CANCER RESEARCH, 2008, 14 (23) :7871-7877
[9]   Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors [J].
Casanovas, O ;
Hicklin, DJ ;
Bergers, G ;
Hanahan, D .
CANCER CELL, 2005, 8 (04) :299-309
[10]   Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins [J].
DePrimo, Samuel E. ;
Bello, Carlo L. ;
Smeraglia, John ;
Baum, Charles M. ;
Spinella, Dominic ;
Rini, Brian I. ;
Michaelson, M. Dror ;
Motzer, Robert J. .
JOURNAL OF TRANSLATIONAL MEDICINE, 2007, 5