Abstract 3854: Precision medicine approach: analysis of renal cancer patient-derived cells with phenomics, genomics and drug sensitivity profiling

Abstract

Abstract We have built up the precision medicine approach for solid tumors to understand biological heterogeneity and driver signalling pathways in cancer, to develop pharmacogenomic biomarkers and to ultimately tailor effective treatments for patients. In addition to genetic profiling of original tumor tissues, we have developed patient -derived tumor cell (PDC) models, and characterized these models with genomics, image-based phenotyping (phenomics) and high throughput drug profiling. Here, we describe our approach for a clear cell renal cell carcinoma (ccRCC) patient. PDC cultures were initiated using conditional reprogramming method from fresh primary tumor, protrusion to vena cava, and the benign tissue samples. The exome-sequencing of tissues and PDCs showed that several copy number variations and somatic driver mutations were shared between the cancer tissue and corresponding cell models, including TSC2 and VHL mutations. Using image-based phenotyping, the PDCs from the benign tissue were observed to be strongly positive to cytokeratin 7 (CK7), while original tumor tissue and PDCs from tumor tissue were predominantly CK7 negative. The PDCs expressed vimentin, a mesenchymal marker, but the epithelial marker E-cadherin was downregulated, suggesting for epithelial-mesenchymal transition. The PDCs from primary tumor were exposed to drug sensitivity profiling with a library of 525 approved and investigational oncology compounds in five different concentrations and imaged for proliferation with Ki-67. PI3K/mTOR pathway inhibitors were found to be among the drugs inhibiting the cell proliferation, in agreement with detected somatic mutations affecting these pathways. In addition, our image-based drug sensitivity testing revealed the intra-sample heterogeneity in drug responses and resistance, and we are now further investigating the mechanisms of most potent drugs and their combinations in PDCs at single cell level. As a conclusion, our results implicate the importance of comprehensive characterization of PDCs and their drug responses in translational research. We also foresee that these approaches may potentially improve the translation of results back to clinic and support the design of combination therapies in cancer. Citation Format: Vilja M. Pietiäinen, Piia Mikkonen, Khalid Saeed, Lassi Paavolainen, Teijo Pellinen, Swapnil Potdar, John Mpindi, Harry Nisén, Antti Rannikko, Tuomas Mirtti, Peter Horvath, Päivi Östling, Olli Kallioniemi. Precision medicine approach: analysis of renal cancer patient-derived cells with phenomics, genomics and drug sensitivity profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3854. doi:10.1158/1538-7445.AM2017-3854