Abstract 44: An in vivo platform of pre-characterized renal cell carcinoma (RCC) patient-derived xenograft models allows the preclinical evaluation of patient-tailored intervention strategies
Authors: Kobelt Dennis , Gürgen Dennis , Becker Michael , Dahlmann Mathias , Flechsig Susanne , Schaeffeler Elke , Büttner Florian A. , Schmees Christian , Bohnert Regina , Bedke Jens , Schwab Matthias , Wendler Johann J. , Schostak Martin , Jandrig Burkhard , Walther Wolfgang , Hoffmann Jens 
Published: April 2023

Renal cell carcinoma (RCC), is the most common kidney cancer of adults, originating in the lining of the proximal convoluted tubule. Prognosis is poor in patients with advanced or metastasized RCC. Drug resistance towards Standard of Care (SoC, incl. everolimus, sorafenib, or sunitinib) drugs develops frequently within months. Therefore, development of novel options to target acquired TKI resistance mechanisms in advanced and metastatic RCC is still an urgent medical need. Preclinical models with high translational relevance can promote the implementation of novel personalized therapies. To evaluate novel targeted therapies and their combinations in preclinical settings, patient-derived xenograft (PDX) models represent valuable tools. Responsible local ethics committees approved usage of patient tissue and all animal procedures. In this study, RCC tissue from 167 patients was collected and xenotransplanted in mice. Partially, a multi-region approach, xenografting tissue from different regions of one tumor, was used. PDX models were characterized by immunohistochemistry (Ki-67, CD31, Pax2 and Pax8 antibodies), gene expression, copy number variations and mutational analyses. To evaluate in vivo drug response of RCC PDX models, mice transplanted with PDX tumors were treated with bevacizumab (i.p.), with everolimus, sorafenib, or sunitinib (p.o.). Adopted clinical response criteria for solid tumors (RECIST) were applied to classify the anti-tumor activity of the tested compounds in RCC PDX models. Next generation sequencing (NGS, panel) and transcriptome data were used to compare primary tumors and metastases. A comprehensive panel of subcutaneous RCC PDX models with well-conserved molecular and pathological features over multiple passages was established. The overall take for the RCC PDX in this study was 21%. Tumor growth characteristics were heterogeneous throughout the different models but were stable during in vivo passaging. Drug screening towards four SoC drugs, targeting the VEGF and PI3K/mTOR pathway, revealed individual and heterogeneous response profiles in the PDX, resembling the clinical situation. Intra-tumor heterogeneity can be assessed via PDX models from multi-tumor regions from one patient in our platform. Development of corresponding in vitro cell culture models from the PDX enables advanced high throughput drug screening in a personalized context. Analyzing novel targeted molecules is possible due to the pre-established molecular characterization of the PDX at the genomic and expression level. In conclusion, we established a new and molecularly characterized panel of RCC PDX models with high relevance for translational preclinical research.

Citation Format: Dennis Kobelt, Dennis Gürgen, Michael Becker, Mathias Dahlmann, Susanne Flechsig, Elke Schaeffeler, Florian A. Büttner, Christian Schmees, Regina Bohnert, Jens Bedke, Matthias Schwab, Johann J. Wendler, Martin Schostak, Burkhard Jandrig, Wolfgang Walther, Jens Hoffmann. An in vivo platform of pre-characterized renal cell carcinoma (RCC) patient-derived xenograft models allows the preclinical evaluation of patient-tailored intervention strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 44.