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 () and Jonathan A. Coleman ()
Additional contact information
Kwanghee Kim: Memorial Sloan Kettering Cancer Center
Wenhuo Hu: Memorial Sloan Kettering Cancer Center
François Audenet: Memorial Sloan Kettering Cancer Center
Nima Almassi: Memorial Sloan Kettering Cancer Center
Aphrothiti J. Hanrahan: Memorial Sloan Kettering Cancer Center
Katie Murray: Memorial Sloan Kettering Cancer Center
Aditya Bagrodia: Memorial Sloan Kettering Cancer Center
Nathan Wong: Memorial Sloan Kettering Cancer Center
Timothy N. Clinton: Memorial Sloan Kettering Cancer Center
Shawn Dason: Memorial Sloan Kettering Cancer Center
Vishnu Mohan: Weizmann Institute of Science
Sylvia Jebiwott: Memorial Sloan Kettering Cancer Center
Karan Nagar: Memorial Sloan Kettering Cancer Center
Jianjiong Gao: Memorial Sloan Kettering Cancer Center
Alex Penson: Memorial Sloan Kettering Cancer Center
Chris Hughes: Memorial Sloan Kettering Cancer Center
Benjamin Gordon: Memorial Sloan Kettering Cancer Center
Ziyu Chen: Memorial Sloan Kettering Cancer Center
Yiyu Dong: Memorial Sloan Kettering Cancer Center
Philip A. Watson: Memorial Sloan Kettering Cancer Center
Ricardo Alvim: Memorial Sloan Kettering Cancer Center
Arijh Elzein: Memorial Sloan Kettering Cancer Center
Sizhi P. Gao: Memorial Sloan Kettering Cancer Center
Emiliano Cocco: Memorial Sloan Kettering Cancer Center
Alessandro D. Santin: Yale University School of Medicine
Irina Ostrovnaya: Memorial Sloan Kettering Cancer Center
James J. Hsieh: Washington University
Irit Sagi: Weizmann Institute of Science
Eugene J. Pietzak: Memorial Sloan Kettering Cancer Center
A. Ari Hakimi: Memorial Sloan Kettering Cancer Center
Jonathan E. Rosenberg: Memorial Sloan Kettering Cancer Center
Gopa Iyer: Memorial Sloan Kettering Cancer Center
Herbert A. Vargas: Memorial Sloan Kettering Cancer Center
Maurizio Scaltriti: Memorial Sloan Kettering Cancer Center
Hikmat Al-Ahmadie: Memorial Sloan Kettering Cancer Center
David B. Solit: Memorial Sloan Kettering Cancer Center
Jonathan A. Coleman: Memorial Sloan Kettering Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15885-7

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