Oncotarget

Research Papers:

Increased PDGFR-beta and VEGFR-2 protein levels are associated with resistance to platinum-based chemotherapy and adverse outcome of ovarian cancer patients

Stefanie Avril, Yasemin Dincer, Katharina Malinowsky, Claudia Wolff, Sibylle Gündisch, Alexander Hapfelmeier, Melanie Boxberg, Holger Bronger, Karl-Friedrich Becker _ and Barbara Schmalfeldt

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Oncotarget. 2017; 8:97851-97861. https://doi.org/10.18632/oncotarget.18415

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Abstract

Stefanie Avril1,4,*, Yasemin Dincer1,*, Katharina Malinowsky1, Claudia Wolff1, Sibylle Gündisch1, Alexander Hapfelmeier2, Melanie Boxberg1, Holger Bronger3, Karl-Friedrich Becker1 and Barbara Schmalfeldt3,5

1Institute of Pathology, Technische Universität München, Munich, Germany

2Institute of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany

3Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany

4Current address: Department of Pathology, Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Cleveland, Ohio, United States

5Current address: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

*These authors contributed equally to this work

Correspondence to:

Karl-Friedrich Becker, email: [email protected]

Keywords: phosphoproteomics, reverse phase protein array (RPPA), ovarian cancer, platinum chemotherapy resistance, response prediction

Received: January 27, 2017     Accepted: May 05, 2017     Published: June 08, 2017

ABSTRACT

Despite frequent initial response rates of epithelial ovarian cancer to platinum-based chemotherapy the majority of patients develop drug resistance. Our aim was to evaluate differential expression of signaling-pathway proteins in platinum-sensitive versus platinum-resistant primary epithelial ovarian cancer specimens to identify predictive biomarkers for treatment response.

192 patients were studied comprising of independent training (n = 89) and validation (n = 103) cohorts. Full-length proteins were extracted from paraffin-embedded samples including multiple regions per tumor to account for intratumoral heterogeneity. Quantitative reverse-phase-protein-arrays were used to analyze protein and phospho-protein levels of 41 signaling molecules including growth-factor receptors, AKT and MAPK signaling pathways as well as angiogenesis and cell-adhesion.

Platinum-resistant ovarian cancers (56/192) demonstrated significantly higher intratumoral levels of the angiogenesis-associated growth-factor receptors PDGFR-beta and VEGFR2 compared to platinum-sensitive tumors. In addition, patients with high PDGFR-beta expression had significantly shorter overall and progression-free survival (HR 3.6 and 2.4; p < 0.001). The prognostic value of PDGFR-beta and VEGFR2 was confirmed in publicly available microarray-datasets.

High intratumoral levels of the angiogenesis-related growth-factor receptors PDGFR-beta and VEGFR2 might serve as novel predictive biomarkers to identify primary resistance to platinum-based chemotherapy. Those ovarian cancer patients might particularly benefit from additional anti-vascular therapy including anti-VEGF antibody or receptor tyrosine-kinase-inhibitor therapy.


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