Abstract
Patient-derived xenografts (PDX) passaged in immunocompromised mice are a well-established system for preclinical efficacy testing of anti-cancer agents. Typically, PDXs are pre-screened ...either in vitro or via molecular analysis, and selected models are then tested in groups of 8 to 12 mice to confirm or evaluate the efficacy of a treatment relative to a vehicle control group. This approach results in highly reliable and reproducible efficacy data. However, it is often desirable to test large panels of tumor models in vivo in order to properly take genetic diversity into account. Such experiments can be cost-prohibitive in conventional study layouts, which results in fewer models being tested.
The Single Mouse Trial (SMT) format addresses the need for compound testing in larger, more diverse tumor populations. This format employs a single mouse per PDX model and treatment arm, thereby enabling the investigation of efficacy in substantially larger panels of PDX models. In order to better mirror inter-patient response diversity observed in the clinic, less emphasis is put on the statistical robustness of response data for individual models.
In the study presented here, six SoC drugs were tested in the SMT format in colorectal (cetuximab, oxaliplatin, irinotecan, 5-FU) and non-small-cell lung cancer (cetuximab, paclitaxel) PDXs, and results were compared to those obtained from standard format experiments with 5 - 10 mice per group. Dosing and schedules were adapted to clinical standards. Data for 19 CXF and 16 NSCLC models showed that in 77% of the cases, results obtained from the single mouse trial format were in line with results from standard efficacy tests. Furthermore, in 10% of the cases, efficacy was similar by trend between the two formats. Notable discrepancies were seen mainly in tumors exhibiting intermediate sensitivity.
Our findings indicate that for the drugs tested here, the risk of misjudging the efficacy in a given PDX model based on SMT is low. This risk could be further lowered by increasing group sizes to 3 mice. For the identification of biomarkers which requires accurate efficacy data, such an intermediate format between the SMT and the standard format might be advantageous.
Citation Format: Christina Gredy, Julia B. Schüler, Nina Zanella, Heinz-Herbert Fiebig, Thomas Metz. Single mouse trials, a concept using patient-derived tumor xenografts for large scale in vivo screens. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2890. doi:10.1158/1538-7445.AM2015-2890
Abstract
Recently, unsupervised gene expression-based signatures with prognostic and potential predictive implications were proposed for colorectal cancer (CRC) classification. The challenge is now ...to characterize the genomic alterations of CRC subtypes and their sensitivity to therapies. Patient derived xenograft models (PDX) may be a valuable tool for this purpose, as they retain the molecular features and drug response patterns of their parental patient tumors. In this study, we classified our collection of colon PDX into transcriptomic subtypes and investigated the associations with genomic alterations and in vivo responses to cetuximab (CTX), oxaliplatin (OXT) and irinotecan (IR). We determined expression profiles of 67 PDX models using Affymetrix HGU133 Plus2.0 arrays and applied the CRC assigner-786 gene expression signature reported by Sadanandam et al. to classify our PDX into 5 subtypes. We identified 34 (51%) transit-amplifying (TA), 15 (22%) goblet-like (GL), 10 (15%) inflammatory (IF), 7 (10%) enterocyte (ET) and 1 (1%) stem-like (SL) PDX models. TA showed a gene signature of WNT pathway activation whereas GL, ET and IF PDX subtypes harbored gene signatures of KRAS pathway activation. As analyzed by whole exome sequencing and Affymetrix SNP6.0 array, the GL, ET and IF subtypes were found to display different signatures of mutational processes, mutations and chromosomal rearrangement patterns than TA and SL. Of particular note, mutations in BRAF, PIK3CA/PTEN, TGFBR2/SMAD4 or NOTCH1 were mainly found in GL, ET or IF while mutations in APC, TP53 and KRAS were not associated with a given subtype. Regarding PDX drug sensitivity, 10/11 TA/SL PDX with unaltered KRAS/PIK3CA/PTEN/HER2 status were sensitive to CTX whereas 9/12 models with alterations were resistant. TA and SL PDX were also frequently sensitive to IR and OXT (6/10 and 4/10, respectively). In the IF subtype, 6/6 PDX showing KRAS, PIK3CA or PTEN alterations were resistant to CTX. Of interest, 5/5 IF PDX were sensitive to IR treatment. As in IF PDX, GL and ET often had alterations in KRAS/PIK3CA/PTEN/HER2 and were resistant to CTX. Moreover, these subtypes were resistant to both IR and OXT. Furthermore, the frequent KRAS pathway activation and the presence of actionable mutations in GL, ET and IF would advocate the testing of inhibitors (as monotherapy or in combination) of BRAF, PI3K or MEK in tumors of these subtypes while WNT inhibitors should be tested in TA models.Molecular classification of our colon PDX collection confirmed their similarities with patient tumors. Investigation of drug sensitivity resulted in the identification of PDX subtypes which respond poorly to standard therapies and which require different treatment options. Testing alternative and combined therapies in PDX may be a valuable approach to optimize personalized medicine.
Citation Format: Anne-Lise Peille, Christina Gredy, Bruno Zeitouni, Armin Maier, Kerstin Klingner, Tim Kees, Julia Schüler, Thomas Metz, Heinz. Herbert Fiebig, Vincent Vuaroqueaux. Classification of colorectal PDX into transcriptomic subtypes associated with distinct genomic alteration profiles and in vivo response patterns to therapies. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1705. doi:10.1158/1538-7445.AM2015-1705
