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Characterizing treatment resistance in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model

BACKGROUND: Non-metastatic muscle invasive urothelial bladder cancer (MIBC) has a poor prognosis and standard of care (SOC) includes neoadjuvant cisplatin-based chemotherapy (NAC) combined with cystectomy. Patients receiving NAC have at best <10% improvement in five-year overall survival compared...

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Autores principales: Villanueva, Hugo, Wells, Gabrielle A., Miller, Malachi T., Villanueva, Mariana, Pathak, Ravi, Castro, Patricia, Ittmann, Michael M., Sikora, Andrew G., Lerner, Seth P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834740/
https://www.ncbi.nlm.nih.gov/pubmed/36643309
http://dx.doi.org/10.1016/j.heliyon.2022.e12570
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author Villanueva, Hugo
Wells, Gabrielle A.
Miller, Malachi T.
Villanueva, Mariana
Pathak, Ravi
Castro, Patricia
Ittmann, Michael M.
Sikora, Andrew G.
Lerner, Seth P.
author_facet Villanueva, Hugo
Wells, Gabrielle A.
Miller, Malachi T.
Villanueva, Mariana
Pathak, Ravi
Castro, Patricia
Ittmann, Michael M.
Sikora, Andrew G.
Lerner, Seth P.
author_sort Villanueva, Hugo
collection PubMed
description BACKGROUND: Non-metastatic muscle invasive urothelial bladder cancer (MIBC) has a poor prognosis and standard of care (SOC) includes neoadjuvant cisplatin-based chemotherapy (NAC) combined with cystectomy. Patients receiving NAC have at best <10% improvement in five-year overall survival compared to cystectomy alone. This major clinical problem underscores gaps in our understanding of resistance mechanisms and a need for reliable pre-clinical models. The chicken embryo chorioallantoic membrane (CAM) represents a rapid, scalable, and cost-effective alternative to immunocompromised mice for establishing patient-derived xenografts (PDX) in vivo. CAM-PDX leverages an easily accessible engraftment scaffold and vascular-rich, immunosuppressed environment for the engraftment of PDX tumors and subsequent functional studies. METHODS: We optimized engraftment conditions for primary MIBC tumors using the CAM-PDX model and tested concordance between cisplatin-based chemotherapy response of patients to matching PDX tumors using tumor growth coupled with immunohistochemistry markers of proliferation and apoptosis. We also tested select kinase inhibitor response on chemotherapy-resistant bladder cancers on the CAM-PDX using tumor growth measurements and immuno-detection of proliferation marker, Ki-67. RESULTS: Our results show primary, NAC-resistant, MIBC tumors grown on the CAM share histological characteristics along with cisplatin-based chemotherapy resistance observed in the clinic for matched parent human tumor specimens. Patient tumor specimens acquired after chemotherapy treatment (post-NAC) and exhibiting NAC resistance were engrafted successfully on the CAM and displayed decreased tumor growth size and proliferation in response to treatment with a dual EGFR and HER2 inhibitor, but had no significant response to either CDK4/6 or FGFR inhibition. CONCLUSIONS: Our data suggests concordance between cisplatin-based chemotherapy resistance phenotypes in primary patient tumors and CAM-PDX models. Further, proteogenomic informed kinase inhibitor use on MIBC CAM-PDX models suggests a benefit from integration of rapid in vivo testing of novel therapeutics to inform more complex, pre-clinical mouse PDX experiments for more effective clinical trial design aimed at achieving optimal precision medicine for patients with limited treatment options.
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spelling pubmed-98347402023-01-13 Characterizing treatment resistance in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model Villanueva, Hugo Wells, Gabrielle A. Miller, Malachi T. Villanueva, Mariana Pathak, Ravi Castro, Patricia Ittmann, Michael M. Sikora, Andrew G. Lerner, Seth P. Heliyon Research Article BACKGROUND: Non-metastatic muscle invasive urothelial bladder cancer (MIBC) has a poor prognosis and standard of care (SOC) includes neoadjuvant cisplatin-based chemotherapy (NAC) combined with cystectomy. Patients receiving NAC have at best <10% improvement in five-year overall survival compared to cystectomy alone. This major clinical problem underscores gaps in our understanding of resistance mechanisms and a need for reliable pre-clinical models. The chicken embryo chorioallantoic membrane (CAM) represents a rapid, scalable, and cost-effective alternative to immunocompromised mice for establishing patient-derived xenografts (PDX) in vivo. CAM-PDX leverages an easily accessible engraftment scaffold and vascular-rich, immunosuppressed environment for the engraftment of PDX tumors and subsequent functional studies. METHODS: We optimized engraftment conditions for primary MIBC tumors using the CAM-PDX model and tested concordance between cisplatin-based chemotherapy response of patients to matching PDX tumors using tumor growth coupled with immunohistochemistry markers of proliferation and apoptosis. We also tested select kinase inhibitor response on chemotherapy-resistant bladder cancers on the CAM-PDX using tumor growth measurements and immuno-detection of proliferation marker, Ki-67. RESULTS: Our results show primary, NAC-resistant, MIBC tumors grown on the CAM share histological characteristics along with cisplatin-based chemotherapy resistance observed in the clinic for matched parent human tumor specimens. Patient tumor specimens acquired after chemotherapy treatment (post-NAC) and exhibiting NAC resistance were engrafted successfully on the CAM and displayed decreased tumor growth size and proliferation in response to treatment with a dual EGFR and HER2 inhibitor, but had no significant response to either CDK4/6 or FGFR inhibition. CONCLUSIONS: Our data suggests concordance between cisplatin-based chemotherapy resistance phenotypes in primary patient tumors and CAM-PDX models. Further, proteogenomic informed kinase inhibitor use on MIBC CAM-PDX models suggests a benefit from integration of rapid in vivo testing of novel therapeutics to inform more complex, pre-clinical mouse PDX experiments for more effective clinical trial design aimed at achieving optimal precision medicine for patients with limited treatment options. Elsevier 2022-12-24 /pmc/articles/PMC9834740/ /pubmed/36643309 http://dx.doi.org/10.1016/j.heliyon.2022.e12570 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Villanueva, Hugo
Wells, Gabrielle A.
Miller, Malachi T.
Villanueva, Mariana
Pathak, Ravi
Castro, Patricia
Ittmann, Michael M.
Sikora, Andrew G.
Lerner, Seth P.
Characterizing treatment resistance in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model
title Characterizing treatment resistance in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model
title_full Characterizing treatment resistance in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model
title_fullStr Characterizing treatment resistance in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model
title_full_unstemmed Characterizing treatment resistance in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model
title_short Characterizing treatment resistance in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model
title_sort characterizing treatment resistance in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834740/
https://www.ncbi.nlm.nih.gov/pubmed/36643309
http://dx.doi.org/10.1016/j.heliyon.2022.e12570
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