Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Nat Commun. 2020 Apr 24;11(1):1975. doi: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Agents / pharmacology
  • Biopsy
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Carcinoma, Transitional Cell / genetics*
  • Carcinoma, Transitional Cell / pathology*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genetic Variation
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoconjugates / pharmacology
  • Interleukin Receptor Common gamma Subunit / genetics
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Mutation
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Phenotype
  • Precision Medicine
  • Prospective Studies
  • Quinolines / pharmacology
  • Retrospective Studies
  • Sequence Analysis, RNA
  • Trastuzumab
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology*
  • Urothelium / pathology*

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Il2rg protein, mouse
  • Immunoconjugates
  • Interleukin Receptor Common gamma Subunit
  • Quinolines
  • trastuzumab deruxtecan
  • neratinib
  • Trastuzumab
  • Camptothecin