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

Kwanghee Kim; Wenhuo Hu; François Audenet; Nima Almassi; Aphrothiti J Hanrahan; Katie Murray; Aditya Bagrodia; Nathan Wong; Timothy N Clinton; Shawn Dason; Vishnu Mohan; Sylvia Jebiwott; Karan Nagar; Jianjiong Gao; Alex Penson; Chris Hughes; Benjamin Gordon; Ziyu Chen; Yiyu Dong; Philip A Watson; Ricardo Alvim; Arijh Elzein; Sizhi P Gao; Emiliano Cocco; Alessandro D Santin; Irina Ostrovnaya; James J Hsieh; Irit Sagi; Eugene J Pietzak; A Ari Hakimi; Jonathan E Rosenberg; Gopa Iyer; Herbert A Vargas; Maurizio Scaltriti; Hikmat Al-Ahmadie; David B Solit; Jonathan A Coleman

doi:10.1038/s41467-020-15885-7

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.

Authors

Kwanghee Kim^#¹, Wenhuo Hu^#², François Audenet³, Nima Almassi³, Aphrothiti J Hanrahan², Katie Murray³, Aditya Bagrodia³, Nathan Wong³, Timothy N Clinton³, Shawn Dason³, Vishnu Mohan⁴, Sylvia Jebiwott¹, Karan Nagar¹, Jianjiong Gao⁵, Alex Penson², Chris Hughes¹, Benjamin Gordon¹, Ziyu Chen², Yiyu Dong², Philip A Watson², Ricardo Alvim¹, Arijh Elzein², Sizhi P Gao², Emiliano Cocco², Alessandro D Santin⁶, Irina Ostrovnaya⁷, James J Hsieh⁸, Irit Sagi⁴, Eugene J Pietzak³, A Ari Hakimi³, Jonathan E Rosenberg⁹, Gopa Iyer⁹, Herbert A Vargas¹⁰, Maurizio Scaltriti², Hikmat Al-Ahmadie¹¹, David B Solit^{12

13

14}, Jonathan A Coleman¹⁵

Affiliations

¹ Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
² Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
³ Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
⁴ Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 7610001, Israel.
⁵ Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
⁶ Gynecology & Reproductive Sciences, Department of Obstetrics, Yale University School of Medicine, New Haven, CT, 06510, USA.
⁷ Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10017, USA.
⁸ Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University, St. Louis, MO, 63110, USA.
⁹ Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
¹⁰ Body Imaging Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
¹¹ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
¹² Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
¹³ Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
¹⁴ Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
¹⁵ Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].

^# Contributed equally.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding