Abstract 1843: Intratumoral heterogeneity of renal cancer is related to differences in drug response and development of therapy resistance
Authors: Becker Michael , Jandrig Burkhard , Flechsig Susanne , Zeisig Reiner , Schindele Daniel , Schostak Martin , Schmees Christian , Wulf-Goldenberg Annika , Hennenlotter Jörg , Schaeffeler Elke , Schwab Matthias , Stenzl Arnulf , Bedke Jens , Hoffmann Jens 
Published: July 2017

Abstract
Background:
Patients with advanced renal cell cancer (RCC) have a poor prognosis not least because of resistance towards standard drugs (SoC). Recently, pronounced intratumoral heterogeneity (ITH) in RCC was shown. We were interested whether this ITH is a potential cause for treatment failure. We developed a large panel of patient-derived xenograft (PDX) models from RCC, including subsets of models from different regions of one individual tumor. The PDX models were evaluated for response to SoC. To better understand correlations between inter- and intratumoral heterogeneity and treatment response, tumor models were panel sequenced and expression profiled.
Methods:
Specimens from primary and metastatic RCCs were collected from consenting patients and transplanted into mice. Tumor engraftment was monitored for up to 4 months. Tumor sections were examined histopathologically to assess concordance between patient tumor and model and were stained for RCC specific markers (Pax2, Pax8, CD31, and RCC). Stable growing PDX were treated with SoC (sunitinib, sorafenib, bevacizumab and everolimus). Global gene expression was analyzed in primary tumors and PDX models using microarrays (Affymetrix). In addition, sequence variations (Illumina NGS cancer panel) and MET and TERT gene copy numbers were analyzed in PDX models.
Results:
A panel of 34 RCC PDX models was established from more than 200 patient samples. Among these, 13 models were derived from different tumor regions of three advanced tumors.
Original patient tumor and PDX showed a very similar and characteristic RCC histopathology. Inter- and intratumoral heterogeneity was preserved for several passages.
We treated all PDX with standard targeted drugs and observed response rates comparable to results from clinical trials. One out of 8 regions obtained from one aggressive RCC clearly differentiated in regard to its response to bevacizumab and sunitinib. Genomic analysis revealed that this region has differences in global gene expression and sequence variation pattern. Besides a common MET mutation an additional variation in the HRAS gene was detected.
In the whole PDX set we found 34 sequence variations in 20 genes, e.g. ATM, MET, TP53 and VHL and copy number variations in the MET locus.
Conclusion:
We have shown that PDX derived from distinct regions within one individual tumor exhibit differences in targeted treatment response as well as in genetic profile. These differences and their correlation to their molecular heterogeneity is subject of ongoing investigations to explain failure in treatment response.
The available panel of renal cancer PDX provides an excellent source for translational research and for preclinical testing of new drug candidates.
Citation Format: Michael Becker, Burkhard Jandrig, Susanne Flechsig, Reiner Zeisig, Daniel Schindele, Martin Schostak, Christian Schmees, Annika Wulf-Goldenberg, Jörg Hennenlotter, Elke Schaeffeler, Matthias Schwab, Arnulf Stenzl, Jens Bedke, Jens Hoffmann. Intratumoral heterogeneity of renal cancer is related to differences in drug response and development of therapy resistance [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 1843. doi:10.1158/1538-7445.AM2017-1843