Molecular tumor heterogeneity in muscle invasive bladder cancer: Biomarkers, subtypes, and implications for therapy

Costa, José Batista da; Gibb, Ewan A.; Nykopp, Timo K.; Mannas, Miles; Wyatt, Alexander W.; Black, Peter C.

doi:10.1016/j.urolonc.2018.11.015

Cited by 35 publications

(56 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 2019, the FGFR inhibitor Balversa (Erdafitinib) was approved by the FDA (Food and Drug Administration) for treatment of patients with metastatic bladder cancer harbouring molecular alterations in FGFR2/3, marking it to be the first targeted therapy to be approved in bladder cancer [7]. Most targeted therapies have shown inconsistent results in early phase clinical trials, which could be attributed to suboptimal selection criteria and biomarker selection, and molecular heterogeneity of the disease [6,8]. Thus, it is not only necessary to identify suitable molecular targets but also predictive markers and combination therapies that broaden the spectrum of responders to treatment.…”

Section: Introductionmentioning

confidence: 99%

STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy

Hindupur

Schmid

Koch

et al. 2020

IJMS

View full text Add to dashboard Cite

The JAK-STAT signalling pathway regulates cellular processes like cell division, cell death and immune regulation. Dysregulation has been identified in solid tumours and STAT3 activation is a marker for poor outcome. The aim of this study was to explore potential therapeutic strategies by targeting this pathway in bladder cancer (BC). High STAT3 expression was detected in 51.3% from 149 patient specimens with invasive bladder cancer by immunohistochemistry. Protein expression of JAK, STAT and downstream targets were confirmed in 10 cell lines. Effects of the JAK inhibitors Ruxolitinib and BSK-805, and STAT3/5 inhibitors Stattic, Nifuroxazide and SH-4-54 were analysed by cell viability assays, immunoblotting, apoptosis and cell cycle progression. Treatment with STAT3/5 but not JAK1/2 inhibitors reduced survival, levels of phosphorylated STAT3 and Cyclin-D1 and increased apoptosis. Tumour xenografts, using the chicken chorioallantoic membrane (CAM) model responded to Stattic monotherapy. Combination of Stattic with Cisplatin, Docetaxel, Gemcitabine, Paclitaxel and CDK4/6 inhibitors showed additive effects. The combination of Stattic with the oncolytic adenovirus XVir-N-31 increased viral replication and cell lysis. Our results provide evidence that inhibitors against STAT3/5 are promising as novel mono- and combination therapy in bladder cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy

Hindupur

Schmid

Koch

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Spatial or temporal heterogeneity of ARID1A mutation and expression appears to be the most common explanation for such discrepancies, as was documented in some of the discordant cases in the current study. Heterogeneity of molecular markers is well known in UC and also paralleled by the notorious heterogeneity of histological appearance . Such heterogeneity makes biomarker testing a challenge because focal alterations can be missed by cytological or histological sampling.…”

Section: Discussionmentioning

confidence: 99%

Immunocytochemistry for ARID1A as a potential biomarker in urine cytology of bladder cancer

Dugas

Müller

Magnen

et al. 2019

Cancer Cytopathology

Self Cite

View full text Add to dashboard Cite

BACKGROUND: Mutations of AT-rich interactive domain 1 (ARID1A) have been associated with a worse outcome after intravesical treatment with bacille Calmette-Guérin in patients with non-muscle-invasive bladder cancer (NMIBC). Loss of ARID1A protein expression in urine cytology may serve as an indication of an ARID1A mutation. Therefore, the authors examined the expression of ARID1A in urine cytology and histological specimens of bladder cancer for correlation with ARID1A mutational status. METHODS: The authors constructed a tissue microarray containing samples from 164 tissue samples from 150 patients with NMIBC and 100 tissue samples from 81 patients with muscle-invasive bladder cancer. A second cohort consisted of archived cytological specimens and matched tissue sections from 62 patients with highgrade NMIBC. The authors established immunohistochemistry and immunocytochemistry (ICC) protocols, respectively, for the analysis of ARID1A protein expression in histological and cytological specimens. Confirmatory next-generation sequencing (NGS) was performed on tumor specimens using a targeted NGS panel containing all exonic regions of ARID1A. RESULTS: The prevalence of ARID1A loss of expression on the tissue microarray was 3.6% in NMIBC (6 of 164 tissue samples) and 10% in muscle-invasive bladder cancer (10 of 100 tissue samples) (P = .059). Loss of ARID1A expression in cytology was concordantly immunohistochemistry negative in 6 of 8 matched tissue specimens. NGS confirmed an ARID1A mutation on all 6 histology samples with loss of ARID1A expression. When NGS demonstrated an absence of ARID1A mutation, histology was concordantly positive (16 of 16 cases). CONCLUSIONS: The authors have suggest ARID1A ICC as a promising surrogate marker for ARID1A mutational status in patients with urothelial carcinoma. Pitfalls in ICC scoring include benign umbrella cells that often are negative for ARID1A. Further prospective studies are needed to determine the clinical relevance of ARID1A ICC in urinary cytology.

show abstract

“…In addition to gene expression profiling, mutational analysis, in particular analysis of mutations in DNA damage repair (DDR) genes (ERCC2, RB1, ATM, and FANCC) have shown prognostic value by selecting for patients who achieve optimal response (ideally pT0) with NAC [6]. Response to platinum-based chemotherapy in the metastatic setting also correlates with DDR mutations [7].…”

Section: Cisplatin-based Chemotherapy For Mibcmentioning

confidence: 99%

Should chemotherapy still be used to treat all muscle invasive bladder cancer in the “era of immunotherapy”?

Duplisea

Dinney

2019

Expert Review of Anticancer Therapy

View full text Add to dashboard Cite

Molecular tumor heterogeneity in muscle invasive bladder cancer: Biomarkers, subtypes, and implications for therapy

Cited by 35 publications

References 53 publications

STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy

STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy

Immunocytochemistry for ARID1A as a potential biomarker in urine cytology of bladder cancer

Should chemotherapy still be used to treat all muscle invasive bladder cancer in the “era of immunotherapy”?

Contact Info

Product

Resources

About