Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts
Open Access
- 24 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-12
- https://doi.org/10.1038/s41467-020-15885-7
Abstract
Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (P50 CA221745, R01 CA234361, P01 CA221757-01A1, P30 CA008748)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
This publication has 54 references indexed in Scilit:
- Deciphering Signatures of Mutational Processes Operative in Human CancerCell Reports, 2013
- The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivityNature, 2012
- RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genomeBMC Bioinformatics, 2011
- MTML-msBayes: Approximate Bayesian comparative phylogeographic inference from multiple taxa and multiple loci with rate heterogeneityBMC Bioinformatics, 2011
- Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trialThe Lancet, 2010
- Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon CancerJournal of Clinical Oncology, 2010
- Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high‐risk upper tract transitional cell carcinomaCancer, 2010
- Genetic Predictors of MEK Dependence in Non–Small Cell Lung CancerCancer Research, 2008
- Establishment and characterization of human urothelial cancer xenografts in severe combined immunodeficient miceInternational Journal of Urology, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005