TY - JOUR
T1 - Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts
AU - Kim, Kwanghee
AU - Hu, Wenhuo
AU - Audenet, François
AU - Almassi, Nima
AU - Hanrahan, Aphrothiti J.
AU - Murray, Katie
AU - Bagrodia, Aditya
AU - Wong, Nathan
AU - Clinton, Timothy N.
AU - Dason, Shawn
AU - Mohan, Vishnu
AU - Jebiwott, Sylvia
AU - Nagar, Karan
AU - Gao, Jianjiong
AU - Penson, Alex
AU - Hughes, Chris
AU - Gordon, Benjamin
AU - Chen, Ziyu
AU - Dong, Yiyu
AU - Watson, Philip A.
AU - Alvim, Ricardo
AU - Elzein, Arijh
AU - Gao, Sizhi P.
AU - Cocco, Emiliano
AU - Santin, Alessandro D.
AU - Ostrovnaya, Irina
AU - Hsieh, James J.
AU - Sagi, Irit
AU - Pietzak, Eugene J.
AU - Hakimi, A. Ari
AU - Rosenberg, Jonathan E.
AU - Iyer, Gopa
AU - Vargas, Herbert A.
AU - Scaltriti, Maurizio
AU - Al-Ahmadie, Hikmat
AU - Solit, David B.
AU - Coleman, Jonathan A.
N1 - Funding Information:
This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, the Thompson Family Foundation, Cycle for Survival, P50 CA221745, R01 CA234361, R01 CA229624-01, U54 OD020355, P01 CA221757-01A1, the Kaufthal Family Bladder Cancer Fund and the NIH/NCI Cancer Center Support Grant P30 CA008748. M.S. was funded by a research grant from Puma Biotechnology and Daiichi-Sankio. We thank Nancy Bouvier, Caitlin Bourque, Ramyasree Madupuri and Ritika Kundra of Marie-Josée and Henry R. Kravis Center for Molecular Oncology of Memorial Sloan Kettering Cancer Center for the management of MSK-IMPACT sequencing data; Dr. Elisa De Stanchina and the MSKCC Anti-tumor assessment core for in vivo studies of HER2-targeting agents; and Dr. Margaret Knowles for kindly providing MGHU3 bladder cancer cell line.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85083832953&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-15885-7
DO - 10.1038/s41467-020-15885-7
M3 - Article
C2 - 32332851
AN - SCOPUS:85083832953
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1975
ER -