Abstract 2978: Generation of drug response data from 57 new patient-derived colon cancer xenografts and 3D cell cultures for systematic correlation with tumor biology within the OncoTrack* project
Authors: Rivera Maria , Keil Marlen , Boehnke Karsten , Lange Martin , Schumacher Dirk , Schäfer Reinhold , Regenbrecht Christian R. , Henderson David , Keilholz Ulrich , Kuehn Alexander , El-Heliebi Amin , Hohensee Tabea , Haybäck Johannes , Reinhard Christoph , Velasco Juan A. , Lehrach Hans , Garin-Chesa Pilar , Beran Garry , Hoffmann Jens 
Published: May 2015

*OncoTrack is a project funded by the Innovative Medicines Initiative Joint Undertaking (IMI JU).

New therapies for colon cancer barely improved cure rates over the last decade and typically only a subset of patients benefits from them. The reasons for these disappointing outcomes are likely related to the inherent genetic and cellular heterogeneity and plasticity of tumors. Therefore only comprehensive approaches that correlate data from systematic molecular tumor tissue characterization with preclinical and clinical responses could improve our understanding of this disease and help to design diagnostic procedures allowing optimal therapy for individual patients.

OncoTrack is an international consortium funded by the Innovative Medicines Initiative (www.OncoTrack.eu) that has launched one of Europe's largest collaborative public-private research projects to implement novel approaches of systems biology into colon cancer therapy.

Tumor tissue and circulating tumor cells from a cohort of more than 120 patients with primary or metastatic colon cancer were subjected to high-throughput protein, epigenome, and gene expression analysis as well as next generation sequencing. Three- dimensional (3D) in vitro cultures and in vivo patient-derived xenografts (PDX) in immunodeficient mice were generated from each tissue sample and used to determine response to more than 14 approved drugs, investigational drug candidates, and tool compounds. These wet-lab data, combined with clinical data were used for in silico modeling to identify new predictors for tailored therapies.

Here we are presenting data from the subproject tumor models and therapy response. Tumor tissues from 118 colon cancer patients (87 primary tumors and 31 metastases) were transplanted into mice. To date, 44 permanent new PDX models have been generated from the primary tumors and 13 from the metastases; (establishment of 25 additional models is ongoing). These models are being used to determine sensitivity of the tumors to a broad range of drugs, targeting signaling pathways frequently activated in cancer. In parallel, in vitro cultures using a Matrigel-based, serum-free 3D system were established and adapted for high-throughput 384-well assay format for testing against a similar drug panel.

Drug response data generated from more than 30 patient specimens using both the specific 3D in vitro assays and the in vivo PDX experiments are available and will be shown and compared.

These experimental results about drug sensitivity together with the molecular signatures of the tumor tissues provide an exceptionally broad basis to analyze the relationship between tumor biology and treatment response. Such approaches may hold promise in the design of rational therapy for colon cancer in the future.

Citation Format: Maria Rivera, Marlen Keil, Karsten Boehnke, Martin Lange, Dirk Schumacher, Reinhold Schäfer, Christian RA Regenbrecht, David Henderson, Ulrich Keilholz, Alexander Kuehn, Amin El-Heliebi, Tabea Hohensee, Johannes Haybäck, Christoph Reinhard, Juan A. Velasco, Hans Lehrach, Pilar Garin-Chesa, Garry Beran, Jens Hoffmann. Generation of drug response data from 57 new patient-derived colon cancer xenografts and 3D cell cultures for systematic correlation with tumor biology within the OncoTrack* project. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2978. doi:10.1158/1538-7445.AM2014-2978