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

Ertl, Iris E; Lemberger, Ursula; Ilijazi, Dafina; Hassler, Melanie R.; Bruchbacher, Andreas; Brettner, Robert; Kronabitter, Hannah; Gutmann, Michael; Vician, Petra; Zeitler, Gerhard; Koren, Anna; Lardeau, Charles-Hugues; Mohr, Thomas; Haitel, Andrea; Compérat, Éva; Oszwald, André; Wasinger, Gabriel; Clozel, Thomas; Elemento, Olivier; Kubicek, Stefan; Berger, Walter; Shariat, Shahrokh F.

doi:10.1016/j.eururo.2022.03.009

Cited by 17 publications

(12 citation statements)

References 34 publications

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“…3H). Interestingly, T24 and TCCSUP cells, which are considered non-type 34,35 , showed a similar behavior to SCaBER when knocked out for CDCP1, with the exception for the 2D proliferation (Supplementary Fig. 2C-F).…”

Section: Transgenic Overexpression Of Cdcp1 Induces Proliferation In ...mentioning

confidence: 77%

CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression

Saponaro

Flottmann

Eckstein

et al. 2023

Sci Rep

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The prognosis of patients with advanced urothelial carcinoma (UC) remains poor and improving treatment continues to be a major medical need. CUB domain containing protein 1 (CDCP1) is a known oncogene in various types of solid cancers and its overexpression is associated with impaired prognosis. However, its role in UC remains undetermined. Here we assessed the clinical relevance of CDCP1 in two cohorts of UC at different stages of the disease. Immunohistochemistry showed that CDCP1 is highly expressed in advanced UC, which significantly correlates with shorter overall survival. Importantly, the basal/squamous UC subtype showed significantly enriched CDCP1 at the mRNA and protein levels. The functional role of CDCP1 overexpression was assessed taking advantage of ex vivo organoids derived from the CDCP1pcLSL/+ transgenic mouse model. Furthermore, CDCP1 knockout UC cell lines were generated using CRISPR/Cas9 technology. Interestingly, CDCP1 overexpression significantly induced the activation of MAPK/ERK pathways in ex vivo organoids and increased their proliferation. Similarly, CDCP1 knockout in UC cell lines reduced their proliferation and migration, concomitant with MAPK/ERK pathway activity reduction. Our results highlight the relevance of CDCP1 in advanced UC and demonstrate its oncogenic role, suggesting that targeting CDCP1 could be a rational therapeutic strategy for the treatment of advanced UC.

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Section: Transgenic Overexpression Of Cdcp1 Induces Proliferation In ...mentioning

confidence: 77%

CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression

Saponaro

Flottmann

Eckstein

et al. 2023

Sci Rep

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“…Cisplatin, Epirubicin, Gemcitabine); as an example, the half-maximal inhibitory concentration value (IC 50 ) for Epirubicin was 10-fold higher in SarBC-01 cells as compared to UroBC-01 cells (IC 50= 0.063 μM vs. 0.006; see complete IC 50 list in Supplementary Table 3 ). Clofarabine, a compound which was recently proposed to be highly effective in bladder cancer subtypes, was among the drugs inhibiting both UroBC-01 and SarBC-01 cells in our screen, albeit with medium efficacy in the SARC model (7) ( Supplementary Table 2 ). Yet top hits for both models were enriched in compounds affecting the mTOR pathway, heat shock proteins, and microtubules ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we address this limitation by establishing a 3D multicellular in vitro model derived from a SARC patient that retains key phenotypical and molecular features of SARC and is tumorigenic in vivo . While few SARC-like models have recently been described (7,14), SarBC-01 represents the first fully characterized long-term organoid model derived from a SARC patient; such type of model better recapitulates heterogeneity than cell lines and is more easily amenable to drug screen than xenografts, making it an attractive model for basic and translational research.…”

Section: Discussionmentioning

confidence: 99%

Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer

Garioni

Blukacz

Nuciforo

et al. 2023

Preprint

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Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of the first long-term 3D organoid-like model derived from a SARC patient (SarBC-01). SarBC-01 emulates aggressive morphological and phenotypical features of SARC and harbor somatic mutations in genes frequently altered in sarcomatoid tumors such as TP53, RB1, and KRAS. High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and organoids derived from a patient with conventional urothelial carcinoma (UroCa), identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, such as agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts, GR was found to be significantly more expressed, at mRNA and protein level, in SARC as compared to UroCa tumor samples. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.

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“…Clofarabine is an anti-metabolic drug used as a third-line treatment for children with acute lymphoblastic leukemia. In an in vitro study, clofarabine was also shown to be effective in remission of BLCA patients (Ertl et al, 2022). Similarly, drugs such as ciclopirox, cytarabine hydrochloride, etoposide have been reported to be effective in the treatment of BLCA (Weir et al, 2021;Kapur et al, 2022;Reyhanoglu and Tadi, 2022).…”

Section: Discussionmentioning

confidence: 95%

A novel cuproptosis-related lncRNAs signature predicts prognostic and immune of bladder urothelial carcinoma

Zhou

Liu

et al. 2023

Front. Genet.

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Bladder Urothelial Carcinoma (BLCA) remains the most common urinary system tumor, and its prognosis is poor. Cuproptosis is a recently discovered novel cell death involved in the development of tumor cells. However, the use of cuproptosis to predict the prognosis and immunity of Bladder Urothelial Carcinoma remains largely unclear, and this study was designed to verify cuproptosis-related long non-coding RNAs (lncRNAs) to estimate the prognosis and immunity of Bladder Urothelial Carcinoma. In our study, we first defined the expression of cuproptosis-related genes (CRGs) in BLCA, and 10 CRGs were up- or downregulated. We then constructed a co-expression network of cuproptosis-related mRNA and long non-coding RNAs using RNA sequence data from The Cancer Genome Atlas Bladder Urothelial Carcinoma (TCGA-BLCA), clinical features and mutation data from BLCA patients to obtain long non-coding RNAs by Pearson analysis. Afterward, univariate and multivariate COX analysis identified 21 long non-coding RNAs as independent prognostic factors and used these long non-coding RNAs to construct a prognostic model. Then, survival analysis, principal component analysis (PCA), immunoassay, and comparison of tumor mutation frequencies were performed to verify the accuracy of the constructed model, and GO and KEGG functional enrichment analysis was used to verify further whether cuproptosis-related long non-coding RNAs were associated with biological pathways. The results showed that the model constructed with cuproptosis-related long non-coding RNAs could effectively evaluate the prognosis of BLCA, and these long non-coding RNAs were involved in numerous biological pathways. Finally, we performed immune infiltration, immune checkpoint and drug sensitivity analyses on four genes (TTN, ARID1A, KDM6A, RB1) that were highly mutated in the high-risk group to evaluate the immune association of risk genes with BLCA. In conclusion, the cuproptosis-related lncRNA markers constructed in this study have evaluation value for prognosis and immunity in BLCA, which can provide a certain reference for the treatment and immunity of BLCA.

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

Cited by 17 publications

References 34 publications

CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression

CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression

Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer

A novel cuproptosis-related lncRNAs signature predicts prognostic and immune of bladder urothelial carcinoma

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