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Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery
Background: Systemic treatment options for metastatic renal cell carcinoma (RCC) have significantly expanded in recent years. However, patients refractory to tyrosine kinase and immune checkpoint inhibitors still have limited treatment options and patient-individualized approaches are largely missin...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227814/ https://www.ncbi.nlm.nih.gov/pubmed/34072926 http://dx.doi.org/10.3390/biomedicines9060627 |
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author | Li, Jielin Pohl, Laura Schüler, Julia Korzeniewski, Nina Reimold, Philipp Kaczorowski, Adam Hou, Weibin Zschäbitz, Stefanie Nientiedt, Cathleen Jäger, Dirk Hohenfellner, Markus Duensing, Anette Duensing, Stefan |
author_facet | Li, Jielin Pohl, Laura Schüler, Julia Korzeniewski, Nina Reimold, Philipp Kaczorowski, Adam Hou, Weibin Zschäbitz, Stefanie Nientiedt, Cathleen Jäger, Dirk Hohenfellner, Markus Duensing, Anette Duensing, Stefan |
author_sort | Li, Jielin |
collection | PubMed |
description | Background: Systemic treatment options for metastatic renal cell carcinoma (RCC) have significantly expanded in recent years. However, patients refractory to tyrosine kinase and immune checkpoint inhibitors still have limited treatment options and patient-individualized approaches are largely missing. Patients and Methods: In vitro drug screening of tumor-derived short-term cultures obtained from seven patients with clear cell RCC was performed. For one patient, a patient-derived xenograft (PDX) mouse model was established for in vivo validation experiments. Drug effects were further investigated in established RCC cell lines. Results: The proteasome inhibitor carfilzomib was among the top hits identified in three of four patients in which an in vitro drug screening could be performed successfully. Carfilzomib also showed significant acute and long-term cytotoxicity in established RCC cell lines. The in vivo antitumoral activity of carfilzomib was confirmed in a same-patient PDX model. The cytotoxicity of carfilzomib was found to correlate with the level of accumulation of ubiquitinated proteins. Conclusions: In this proof-of-concept study, we show that patient-individualized in vitro drug screening and preclinical validation is feasible. However, the fact that carfilzomib failed to deliver a clinical benefit in RCC patients in a recent phase II trial unrelated to the present study underscores the complexities and limitations of this strategy. |
format | Online Article Text |
id | pubmed-8227814 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82278142021-06-26 Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery Li, Jielin Pohl, Laura Schüler, Julia Korzeniewski, Nina Reimold, Philipp Kaczorowski, Adam Hou, Weibin Zschäbitz, Stefanie Nientiedt, Cathleen Jäger, Dirk Hohenfellner, Markus Duensing, Anette Duensing, Stefan Biomedicines Article Background: Systemic treatment options for metastatic renal cell carcinoma (RCC) have significantly expanded in recent years. However, patients refractory to tyrosine kinase and immune checkpoint inhibitors still have limited treatment options and patient-individualized approaches are largely missing. Patients and Methods: In vitro drug screening of tumor-derived short-term cultures obtained from seven patients with clear cell RCC was performed. For one patient, a patient-derived xenograft (PDX) mouse model was established for in vivo validation experiments. Drug effects were further investigated in established RCC cell lines. Results: The proteasome inhibitor carfilzomib was among the top hits identified in three of four patients in which an in vitro drug screening could be performed successfully. Carfilzomib also showed significant acute and long-term cytotoxicity in established RCC cell lines. The in vivo antitumoral activity of carfilzomib was confirmed in a same-patient PDX model. The cytotoxicity of carfilzomib was found to correlate with the level of accumulation of ubiquitinated proteins. Conclusions: In this proof-of-concept study, we show that patient-individualized in vitro drug screening and preclinical validation is feasible. However, the fact that carfilzomib failed to deliver a clinical benefit in RCC patients in a recent phase II trial unrelated to the present study underscores the complexities and limitations of this strategy. MDPI 2021-05-31 /pmc/articles/PMC8227814/ /pubmed/34072926 http://dx.doi.org/10.3390/biomedicines9060627 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Li, Jielin Pohl, Laura Schüler, Julia Korzeniewski, Nina Reimold, Philipp Kaczorowski, Adam Hou, Weibin Zschäbitz, Stefanie Nientiedt, Cathleen Jäger, Dirk Hohenfellner, Markus Duensing, Anette Duensing, Stefan Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery |
title | Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery |
title_full | Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery |
title_fullStr | Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery |
title_full_unstemmed | Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery |
title_short | Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery |
title_sort | targeting the proteasome in advanced renal cell carcinoma: complexity and limitations of patient-individualized preclinical drug discovery |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227814/ https://www.ncbi.nlm.nih.gov/pubmed/34072926 http://dx.doi.org/10.3390/biomedicines9060627 |
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