Analysis of the antineoplastic action of Class I HDAC inhibitors to define new combination therapies for urothelial carcinoma
Final Report Abstract
Patients with muscle-invasive growing urothelial carcinoma (UC) experience an aggressive course. Due to therapy resistance, standard chemotherapy and modern immunotherapies hardly improve tumor-specific long-term survival. New therapeutic approaches are urgently needed. Our approach is to use pharmacological inhibitors of epigenetic enzymes such as histone deacetylases (HDACi), especially class I enzymes. Since our lead compound romidepsin (Romi) was poorly tolerated by benign control cells, this project should test 1) other commercial HDACi and 2) new HDACi developed at HHU for their better suitability (similar antineoplastic effects with lower normal toxicity). Since synergistic effects of a combination treatment allow dose reduction, suitable combination partners for class I HDACi should be tested in vitro and in vivo. Compared to Romi, Entinostat and RGFP966 were less effective. Quisinostat (Quisi) showed a better efficacy profile in terms of cell death induction and normal tolerance. It had a strong synergistic effect in combination with cisplatin or the PARP inhibitor Talazoparib, even in cisplatin-resistant UC cell lines and in vivo. The project enabled the development of 2 new effective combination therapies, which will be further tested for clinical translation, including in chemotherapy-resistant settings. Following the screening analysis of new HDACi, 6 compounds were characterized in detail. They had comparable antineoplastic effects to Romi, but were better tolerated by benign cells. Combination with cisplatin was synergistic, suitability for further combination approaches will be tested in the future. We identified new HDACi with a better efficacy profile for UC therapy approaches.
Publications
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Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells. Genes, 12(2), 260.
Hoffmann, Michèle J.; Meneceur, Sarah; Hommel, Katrin; Schulz, Wolfgang A. & Niegisch, Günter
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Epigenetic Priming of Bladder Cancer Cells With Decitabine Increases Cytotoxicity of Human EGFR and CD44v6 CAR Engineered T-Cells. Frontiers in Immunology, 12.
Grunewald, Camilla M.; Haist, Corinna; König, Carolin; Petzsch, Patrick; Bister, Arthur; Nößner, Elfriede; Wiek, Constanze; Scheckenbach, Kathrin; Köhrer, Karl; Niegisch, Günter; Hanenberg, Helmut & Hoffmann, Michèle J.
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Epigenetic Treatment of Urothelial Carcinoma Cells Sensitizes to Cisplatin Chemotherapy and PARP Inhibitor Treatment. Cancers, 13(6), 1376.
Thy, Sophia; Hommel, Alexandra; Meneceur, Sarah; Bartkowiak, Anna L.; Schulz, Wolfgang A.; Niegisch, Günter & Hoffmann, Michèle J.
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AUF-Symposium der DGU 2022: “Overcoming cisplatin resistance of cisplatin resistant urothelial cancer cell lines by treatment with histone deacetylase inhibitor quisinostat.”
Meneceur S., Hoffmann M.J. & Niegisch G.
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Proteomic and transcriptomic profiles of human urothelial cancer cells with histone deacetylase 5 overexpression. Scientific Data, 9(1).
Jaguva, Vasudevan Ananda Ayyappan; Hoffmann, Michèle J.; Poschmann, Gereon; Petzsch, Patrick; Wiek, Constanze; Stühler, Kai; Köhrer, Karl; Schulz, Wolfgang A. & Niegisch, Günter
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AUF-Symposium der DGU 2023: „Identifizierung neuer Histondeacetylase-Inhibitoren mit verbesserter tumorspezifischer Wirkung zur Behandlung von Urothelkarzinom- Zellen.“
Tanjaya F., Hansen F.K., Stenzel K., Asfaha Y., Meneceur S., Kurz T., Niegisch G. & Hoffmann M.J.
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AUF-Symposium der DGU 2023: „Neu entwickelte HDAC-Inhibitoren mit stärker tumorspezifischer Wirkung induzieren Mitosestörungen in Urothelkarzinomzellen.“
Khatib H., Fischer F., Avelar L.A.A., Thieltges V., Meneceur S., Kurz T., Niegisch G. & Hoffmann M.J.
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Epigenetic Priming and Development of New Combination Therapy Approaches. Methods in Molecular Biology, 259-281. Springer US.
Meneceur, Sarah; Grunewald, Camilla M.; Niegisch, Günter & Hoffmann, Michèle J.
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Europäischer Krebskongress (EACR) 2023: pEACR23-0791: “Evaluation of the second generation histone deacetylase inhibitor (HDACi) quisinostat as therapeutic option to overcome cisplatin resistance”
Meneceur S., Hoffmann M.J. & Niegisch G.
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Jahreskongress der dt. Gesellschaft für Urologie (DGU) 2023: “The second generation histone deacetylase inhibitor (HDACi) quisinostat (QUISI) as therapeutic option in urothelial cancer – initial in vivo evaluation”
Meneceur S., Hoffmann M.J. & Niegisch G.
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New synergistic combination therapy approaches with HDAC inhibitor quisinostat, cisplatin or PARP inhibitor talazoparib for urothelial carcinoma. Journal of Cellular and Molecular Medicine, 28(9).
Meneceur, Sarah; De Vos, Caroline E.; Petzsch, Patrick; Köhrer, Karl; Niegisch, Günter & Hoffmann, Michèle J.
