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Molecular and Pharmacological Bladder Cancer Therapy Screening: Discovery of Clofarabine as a Highly Active Compound

IE. Ertl, U. Lemberger, D. Ilijazi, MR. Hassler, A. Bruchbacher, R. Brettner, H. Kronabitter, M. Gutmann, P. Vician, G. Zeitler, A. Koren, CH. Lardeau, T. Mohr, A. Haitel, E. Compérat, A. Oszwald, G. Wasinger, T. Clozel, O. Elemento, S. Kubicek,...

. 2022 ; 82 (3) : 261-270. [pub] 20220404

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc22024569

BACKGROUND: The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. OBJECTIVE: We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. DESIGN, SETTING, AND PARTICIPANTS: A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. RESULTS AND LIMITATIONS: Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8). CONCLUSIONS: The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. PATIENT SUMMARY: We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.

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$a BACKGROUND: The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. OBJECTIVE: We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. DESIGN, SETTING, AND PARTICIPANTS: A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. RESULTS AND LIMITATIONS: Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8). CONCLUSIONS: The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. PATIENT SUMMARY: We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.
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$a Hassler, Melanie R $u Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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$a Bruchbacher, Andreas $u Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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$a Brettner, Robert $u Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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$a Kronabitter, Hannah $u Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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$a Gutmann, Michael $u Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
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$a Vician, Petra $u Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
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$a Zeitler, Gerhard $u Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
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$a Koren, Anna $u CeMM Research Center for Molecular Medicine, Vienna, Austria
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$a Lardeau, Charles-Hugues $u CeMM Research Center for Molecular Medicine, Vienna, Austria
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$a Mohr, Thomas $u Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
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$a Haitel, Andrea $u Department of Pathology, Medical University of Vienna, Vienna, Austria
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$a Compérat, Eva $u Department of Pathology, Medical University of Vienna, Vienna, Austria
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$a Oszwald, André $u Department of Pathology, Medical University of Vienna, Vienna, Austria
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$a Wasinger, Gabriel $u Department of Pathology, Medical University of Vienna, Vienna, Austria
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$a Clozel, Thomas $u OWKIN, New York City, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY, USA
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$a Elemento, Olivier $u Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
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$a Kubicek, Stefan $u CeMM Research Center for Molecular Medicine, Vienna, Austria
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$a Berger, Walter $u Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria. Electronic address: walter.berger@meduniwien.ac.at
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$a Shariat, Shahrokh F $u Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Department of Urology, University of Texas Southwestern, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan
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