Patient derived renal cell carcinoma xenografts exhibit distinct sensitivity patterns in response to antiangiogenic therapy and constitute a suitable tool for biomarker development

// Julia Schueler 1 , Kerstin Klingner 1 , Daniel Bug 3 , Caren Zoeller 7 , Armin Maier 1 , Meng Dong 8 , Kerstin Willecke 8 , Anne-Lise Peille 1 , Eva Steiner 4 , Manuel Landesfeind 1 , John A. Copland 2 , Gabrielle M. Siegers 6 , Axel Haferkamp 5 , Katharina Boehm 5 , Igor Tsaur 5 and Meike Schneider 5 1 Charles River Discovery Research Services Germany GmbH, Freiburg, Germany 2 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA 3 LfB – Lehrstuhl fur Bildverarbeitung, RWTH Aachen University, Aachen, Germany 4 Department of Urology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany 5 Department of Urology, Medical Center Johannes Gutenberg University, Mainz, Germany 6 Department of Experimental Oncology, University of Alberta, 5-142W Katz Group Centre, Edmonton, Canada 7 Department of Radiation Oncology, University Hospital of Wurzburg, Wurzburg, Germany 8 Dr. Margarete Fischer-Bosch - Institut fur Klinische Pharmakologie, Stuttgart, Germany Correspondence to: Meike Schneider, email: meikeschneider310@gmail.com Keywords: HMGB1; renal cell carcinoma; damage associated molecular pattern; bevacizumab; VEGF Received: November 11, 2017     Accepted: June 12, 2018     Published: July 24, 2018 ABSTRACT Systemic treatment is necessary for one third of patients with renal cell carcinoma. No valid biomarker is currently available to tailor personalized therapy. In this study we established a representative panel of patient derived xenograft (PDX) mouse models from patients with renal cell carcinomas and determined serum levels of high mobility group B1 (HMGB1) protein under treatment with sunitinib, pazopanib, sorafenib, axitinib, temsirolimus and bevacizumab. Serum HMGB1 levels were significantly higher in a subset of the PDX collection, which exhibited slower tumor growth during subsequent passages than tumors with low HMGB1 serum levels. Pre-treatment PDX serum HMGB1 levels also correlated with response to systemic treatment: PDX models with high HMGB1 levels predicted response to bevacizumab. Taken together, we provide for the first time evidence that the damage associated molecular pattern biomarker HMGB1 can predict response to systemic treatment with bevacizumab. Our data support the future evaluation of HMGB1 as a predictive biomarker for bevacizumab sensitivity in patients with renal cell carcinoma.