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Updated: Apr 17, 2026
Orthotopic Implantation of Patient-Derived Cancer Cells in Mice Recapitulates Advanced Colorectal Cancer
Published on: February 10, 2023
Evaluating patient-derived colorectal cancer xenografts as preclinical models by comparison with patient clinical
Manoel Nunes1, Patricia Vrignaud1, Sophie Vacher2
1Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Vitry-sur-Seine, France. Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Cambridge, Massachusetts.
Abstract:
Development of targeted therapeutics required translationally relevant preclinical models with well-characterized cancer genome alterations. Here, by studying 52 colorectal patient-derived tumor xenografts (PDX), we examined key molecular alterations of the IGF2-PI3K and ERBB-RAS pathways and response to cetuximab. PDX molecular data were compared with that published for patient colorectal tumors in The Cancer Genome Atlas. We demonstrated a significant pattern of mutual exclusivity of genomic abnormalities in the IGF2-PI3K and ERBB-RAS pathways. The genomic anomaly frequencies observed in microsatellite stable PDX reproduce those detected in nonhypermutated patient tumors. We found frequent IGF2 upregulation (16%), which was mutually exclusive with IRS2, PIK3CA, PTEN, and INPP4B alterations, supporting IGF2 as a potential drug target. In addition to maintaining the genomic and histologic diversity, correct preclinical models need to reproduce drug response observed in patients. Responses of PDXs to cetuximab recapitulate also clinical data in patients, with partial or complete response in 15% (8 of 52) of PDXs and response strictly restricted to KRAS wild-type models. The response rate reaches 53% (8 of 15) when KRAS, BRAF, and NRAS mutations are concomitantly excluded, proving a functional cross-validation of predictive biomarkers obtained retrospectively in patients. Collectively, these results show that, because of their clinical relevance, colorectal PDXs are appropriate tools to identify both new targets, like IGF2, and predictive biomarkers of response/resistance to targeted therapies.
Insights
Patient-derived tumor xenografts (PDX) accurately model colorectal cancer (CRC) molecular profiles and drug responses. These models identified Insulin-like Growth Factor 2 (IGF2) as a potential therapeutic target and validated predictive biomarkers for targeted therapies.
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Targeted cancer therapies require preclinical models that accurately reflect human tumor molecular characteristics.
- Patient-derived tumor xenografts (PDX) are valuable tools for studying cancer, but their translational relevance needs validation.
Purpose of the Study:
- To investigate the molecular alterations in the IGF2-PI3K and ERBB-RAS pathways within colorectal cancer (CRC) patient-derived tumor xenografts (PDX).
- To assess the response of these PDX models to cetuximab and compare findings with The Cancer Genome Atlas (TCGA) data.
- To identify potential new drug targets and predictive biomarkers for CRC targeted therapies.
Main Methods:
- Analysis of 52 colorectal PDX models, including molecular profiling of IGF2-PI3K and ERBB-RAS pathways.
- Comparison of PDX genomic data with The Cancer Genome Atlas (TCGA) database for colorectal tumors.
- Evaluation of PDX response to cetuximab treatment and correlation with specific genetic mutations (KRAS, BRAF, NRAS).
Main Results:
- A significant mutual exclusivity was observed between genomic alterations in the IGF2-PI3K and ERBB-RAS pathways.
- Frequent Insulin-like Growth Factor 2 (IGF2) upregulation (16%) was found, mutually exclusive with alterations in IRS2, PIK3CA, PTEN, and INPP4B.
- Cetuximab response in PDX models (15%) mirrored clinical data, with responses strictly limited to KRAS wild-type models, achieving 53% when BRAF and NRAS mutations were also excluded.
Conclusions:
- Colorectal PDX models exhibit high translational relevance, accurately reflecting patient tumor genomics and drug responses.
- IGF2 is a potential therapeutic target in colorectal cancer due to its frequent upregulation and mutual exclusivity with other pathway alterations.
- PDX models are effective tools for identifying novel drug targets and validating predictive biomarkers for targeted therapies in colorectal cancer.
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