PURPOSE OF REVIEW: Bladder cancer (BC) is a highly heterogenous disease comprising tumours of various molecular subtypes and histologic variants. This heterogeneity represents a major challenge for the development of novel therapeutics. Preclinical models that closely mimic in vivo tumours and reflect their diverse biology are indispensable for the identification of therapies with specific activity in various BC subtypes. In this review, we summarize efforts and progress made in this context during the last 24 months. RECENT FINDINGS: In recent years, one main focus was laid on the development of patient-derived BC models. Patient-derived organoids (PDOs) and patient-derived xenografts (PDXs) were demonstrated to widely recapitulate the molecular and histopathological characteristics, as well as the drug response profiles of the corresponding tumours of origin. These models, thus, represent promising tools for drug development and personalized medicine. Besides PDXs, syngenic in vivo models are of growing importance. Since these models are generated using immunocompetent hosts, they can, amongst others, be used to develop novel immunotherapeutics and to evaluate the impact of the immune system on drug response and resistance. SUMMARY: In the past two years, various in vivo and in vitro models closely recapitulating the biology and heterogeneity of human bladder tumours were developed.

Center for Cancer Research Medical University of Vienna Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University Prag Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology University of Texas Southwestern Dallas Texas USA

Department of Urology Weill Cornell Medical College New York New York

Division of Urology Department of Special Surgery Jordan University Hospital The University of Jordan Amman Jordan

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Research Center for Evidence Medicine Urology Department Tabriz University of Medical Sciences Tabriz Iran

Zobrazit více v PubMed

Sung H, Ferlay J, Siegel RL, et al. . Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71:209–249. PubMed

Roubal K, Myint ZW, Kolesar JM. Erdafitinib: a novel therapy for FGFR-mutated urothelial cancer. Am J Health-Syst Pharm 2020; 77:346–351. PubMed

Lopez-Beltran A, Cimadamore A, Blanca A, et al. . Immune checkpoint inhibitors for the treatment of bladder Cancer. Cancers 2021; 13:E131. PubMed PMC

Maas M, Stühler V, Walz S, et al. . Enfortumab vedotin – next game-changer in urothelial cancer. Expert Opin Biol Ther 2021; 21:801–809. PubMed

Lobo N, Shariat SF, Guo CC, et al. . What is the significance of variant histology in urothelial carcinoma? Eur Urol Focus 2020; 6:653–663. PubMed

Damrauer JS, Hoadley KA, Chism DD, et al. . Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 2014; 111:3110–3115. PubMed PMC

Choi W, Porten S, Kim S, et al. . Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014; 25:152–165. PubMed PMC

Mitra A, Mishra L, Li S. Technologies for deriving primary tumor cells for use in personalized cancer therapy. Trends Biotechnol 2013; 31:347–354. PubMed PMC

Gillet J-P, Calcagno AM, Varma S, et al. . Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anticancer drug resistance. Proc Natl Acad Sci USA 2011; 108:18708–18713. PubMed PMC

Wang H, Brown PC, Chow ECY, et al. . 3D cell culture models: drug pharmacokinetics, safety assessment, and regulatory consideration. Clin Transl Sci 2021; 14:1659–1680. PubMed PMC

Neuhaus J, Rabien A, Reinhold A, et al. . 3D tumor models in urology. Int J Mol Sci 2023; 24:6232. PubMed PMC

Berndt-Paetz M, Han S, Weimann A, et al. . Cell line-based human bladder organoids with bladder-like self-organization—a new standardized approach in bladder cancer research. Biomedicines 2023; 11:2958. PubMed PMC

Wei Y, Amend B, Todenhöfer T, et al. . Urinary tract tumor organoids reveal eminent differences in drug sensitivities when compared to 2-dimensional culture systems. Int J Mol Sci 2022; 23:6305. PubMed PMC

Minoli M, Cantore T, Hanhart D, et al. . Bladder cancer organoids as a functional system to model different disease stages and therapy response. Nat Commun 2023; 14:2214. PubMed PMC

Seiler R, Egger M, De Menna M, et al. . Guidance of adjuvant instillation in intermediate-risk nonmuscle invasive bladder cancer by drug screens in patient derived organoids: a single center, open-label, phase II trial. BMC Urol 2023; 23:89. PubMed PMC

Garioni M, Tschan VJ, Blukacz L, et al. . Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer. Npj Precis Oncol 2023; 7:112. PubMed PMC

Jiang Y, Sun X, Song X, et al. . Patient-derived bladder cancer organoid model to predict sensitivity and feasibility of tailored precision therapy. Curr Urol 2023; 17:221–228. PubMed PMC

Zhao Z, Zhang S, Jiang N, et al. . Patient-derived immunocompetent tumor organoids: a platform for chemotherapy evaluation in the context of t-cell recognition. Angew Chem Int Ed Engl 2024; 63:e202317613. PubMed

Viergever BJ, Raats DAE, Geurts V, et al. . Urine-derived bladder cancer organoids (urinoids) as a tool for cancer longitudinal response monitoring and therapy adaptation. Br J Cancer 2024; 130:369–379. PubMed PMC

Walz S, Pollehne P, Geng R, et al. . A protocol for organoids from the urine of bladder cancer patients. Cells 2023; 12:2188. PubMed PMC

Becker L, Fischer F, Fleck JL, et al. . Data-driven identification of biomarkers for in situ monitoring of drug treatment in bladder cancer organoids. Int J Mol Sci 2022; 23:6956. PubMed PMC

Zhang S, Li L, Yu P, et al. . A deep learning model for drug screening and evaluation in bladder cancer organoids. Front Oncol 2023; 13:1064548. PubMed PMC

Jäger W, Moskalev I, Raven P, et al. Orthotopic mouse models of urothelial cancer. In: Schulz WA, Hoffmann MJ, Niegisch G, editors. Urothelial carcinoma: methods and protocols. Springer; 2018:177–197. PubMed

Zhu S, Zhu Z, Ma A-H, et al. . Preclinical models for bladder cancer research. Hematol Oncol Clin North Am 2021; 35:613–632. PubMed PMC

Lang H, Béraud C, Cabel L, et al. . Integrated molecular and pharmacological characterization of patient-derived xenografts from bladder and ureteral cancers identifies new potential therapies. Front Oncol 2022; 12:930731. PubMed PMC

Steele TM, Tsamouri MM, Siddiqui S, et al. . Cisplatin-induced increase in heregulin 1 and its attenuation by the monoclonal ErbB3 antibody seribantumab in bladder cancer. Sci Rep 2023; 13:9617. PubMed PMC

Laranjeira ABA, Hollingshead MG, Nguyen D, et al. . DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors. Sci Rep 2023; 13:5964. PubMed PMC

Kowald S, Huge Y, Tandiono D, et al. . Novel zebrafish patient-derived tumor xenograft methodology for evaluating efficacy of immune-stimulating bcg therapy in urinary bladder cancer. Cells 2023; 12:508. PubMed PMC

Villanueva H, Wells GA, Miller MT, et al. . Characterizing treatment resistance in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model. Heliyon 2022; 8:e12570. PubMed PMC

Domingos-Pereira S, Sathiyanadan K, Polak L, et al. . Tumor-microenvironment characterization of the MB49 non-muscle-invasive bladder-cancer orthotopic model towards new therapeutic strategies. Int J Mol Sci 2022; 24:123. PubMed PMC

Denis M, Grasselly C, Choffour P-A, et al. . In vivo syngeneic tumor models with acquired resistance to anti-PD-1/PD-L1 therapies. Cancer Immunol Res 2022; 10:1013–1027. PubMed

Dominguez-Gutierrez PR, Kwenda EP, Donelan W, et al. . Detection of PD-L1-expressing myeloid cell clusters in the hyaluronan-enriched stroma in tumor tissue and tumor-draining lymph nodes. J Immunol 2022; 208:2829–2836. PubMed

Xu D, Wang L, Wieczorek K, et al. . Single-cell analyses of a novel mouse urothelial carcinoma model reveal a role of tumor-associated macrophages in response to anti-PD-1 therapy. Cancers 2022; 14:2511. PubMed PMC

Tsuji S, Reil K, Nelson K, et al. . Intravesical VAX014 synergizes with PD-L1 blockade to enhance local and systemic control of bladder cancer. Cancer Immunol Res 2022; 10:978–995. PubMed PMC

Huang C-P, Lu H-L, Shyr C-R. Antitumor activity of intratumoral xenogeneic urothelial cell monotherapy or in combination with chemotherapy in syngeneic murine models of bladder cancer. Am J Cancer Res 2023; 13:2285–2306. PubMed PMC

Bazargan S, Bunch B, Ojwang‘ AME, et al. . Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer. Front Immunol 2023; 14: PubMed PMC

Wong JL, Smith P, Angulo-Lozano J, et al. . IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer. Proc Natl Acad Sci USA 2023; 120:e2306782120. PubMed PMC

Alfred Witjes J, Max Bruins H, Carrión A, et al. . European Association of Urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2023 guidelines. Eur Urol 2024; 85:17–31. PubMed

Shah SD, Gillard BM, Wrobel MM, et al. . Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancer. Front Oncol 2023; 13:1120329. PubMed PMC

Wang S-C, Yu C-Y, Wu Y-C, et al. . Chidamide and mitomycin C exert synergistic cytotoxic effects against bladder cancer cells in vitro and suppress tumor growth in a rat bladder cancer model. Cancer Lett 2022; 530:8–15. PubMed

Piunti A, Meghani K, Yu Y, et al. Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma. Sci Adv 8:eabo8043. PubMed PMC