scholarly journals Organoid model of urothelial cancer: establishment and applications for bladder cancer research

BioTechniques ◽  
2020 ◽  
Vol 69 (3) ◽  
pp. 193-199
Author(s):  
Terry Whyard ◽  
Jingxuan Liu ◽  
Frank S Darras ◽  
Wayne C Waltzer ◽  
Victor Romanov
Keyword(s):  
Bladder Cancer ◽  
Anticancer Agents ◽  
Drug Response ◽  
Urothelial Cancer ◽  
Drug Evaluation ◽  
Drug Application ◽  
Tissue Architecture ◽  
Background Signal ◽  
Simple Modification ◽  
Plating Density

3D cancer cell models are suitable for drug evaluation because they more precisely mimic tissue architecture than 2D cultures. To study cytotoxicity of anticancer agents, the most sensitive CellTiter-Glo 3D assay is used. However, this is an end point assay, so it is not possible to consider the variance of the starting material amount in the final reading. It is difficult to maintain an even plating density of 3D organoids for cytotoxicity analysis. We present a simple, 3D bladder cancer culture that can be maintained, cryopreserved and used for molecular and drug response studies. We applied a simple modification of the drug response assay for 3D cultures by measuring the background signal with the CellTiter Blue assay before drug application.

scholarly journals A showcase study on personalized in silico drug response prediction based on the genetic landscape of muscle invasive bladder cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Friedemann Krentel ◽  
Franziska Singer ◽  
María Lourdes Rosano-Gonzalez ◽  
Ewan A. Gibb ◽  
Yang Liu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
In Silico ◽  
Drug Response ◽  
Gene Interaction ◽  
Response Prediction ◽  
Manual Curation ◽  
Genetic Landscape ◽  
Promising Treatment ◽  
Muscle Invasive ◽  
The Individual

AbstractImproved and cheaper molecular diagnostics allow the shift from “one size fits all” therapies to personalised treatments targeting the individual tumor. However, the wealth of potential targets based on comprehensive sequencing remains a yet unsolved challenge that prevents its routine use in clinical practice. Thus, we designed a workflow that selects the most promising treatment targets based on multi-omics sequencing and in silico drug prediction. In this study we demonstrate the workflow with focus on bladder cancer (BLCA), as there are, to date, no reliable diagnostics available to predict the potential benefit of a therapeutic approach. Within the TCGA-BLCA cohort, our workflow identified a panel of 21 genes and 72 drugs that suggested personalized treatment for 95% of patients—including five genes not yet reported as prognostic markers for clinical testing in BLCA. The automated predictions were complemented by manually curated data, thus allowing for accurate sensitivity- or resistance-directed drug response predictions. We discuss potential improvements of drug-gene interaction databases on the basis of pitfalls that were identified during manual curation.

scholarly journals Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1169
Author(s):  
Hiroki Ide ◽  
Hiroshi Miyamoto
Keyword(s):  
Bladder Cancer ◽  
Estrogen Receptor ◽  
Androgen Receptor ◽  
Surgical Therapy ◽  
Urothelial Cancer ◽  
Hormone Receptors ◽  
Estrogen Receptor Α ◽  
Vital Role ◽  
Sex Hormone ◽  
Sex Steroid Hormone

There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic and anti-estrogenic drugs, apart from their direct anti-tumor activity, to function as sensitizers of such conventional treatment. This article summarizes available data suggesting the involvement of sex hormone receptors, such as androgen receptor, estrogen receptor-α, and estrogen receptor-β, in the progression of urothelial cancer, focusing on their modulation for the efficacy of conventional therapy, and discusses their potential of overcoming therapeutic resistance.

Neoadjuvant or adjuvant immunotherapy in bladder cancer: biological opportunity or clinical utility?

2021 ◽  
pp. 030089162110616
Author(s):  
Fausto Petrelli ◽  
Gianluca Perego ◽  
Ivano Vavassori ◽  
Andrea Luciani
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Cancer Of The Bladder ◽  
Muscle Invasive

In urothelial cancer of the bladder, the introduction of immunotherapy with immune checkpoint inhibitors represents progress in the management of the disease’s early and advanced stages. In particular, recent studies have implemented these drugs in the neoadjuvant and adjuvant phases to treat muscle-invasive bladder cancer. In some studies, patients received neoadjuvant immune checkpoint inhibitors alone (PURE and ABACUS) to treat muscle invasive bladder cancer, whereas other studies provided this therapy to cisplatin-ineligible patients. Furthermore, a large Phase III study (CheckMate 247) compared placebo with adjuvant nivolumab therapy in patients with high-risk urothelial cancer after neoadjuvant chemotherapy and surgery or surgery alone. Despite some uncertain niches (nonbladder, PD-L1-negative tumors, and node-negative resected cancers), certain biological opportunities (exploring new targets, evaluating in vivo pathologic response, focusing on biomarkers for response) and clinical uses (avoiding chemotherapy at all or in frail patients, attaining similar pathologic complete response rates as in cisplatin-based chemotherapy) are valid reasons for incorporating these agents into the therapeutic armamentarium of medical uro-oncologists.

Treatment of metastatic bladder cancer

2017 ◽  
Author(s):  
Fabio Calabrò ◽  
Cora N. Sternberg
Keyword(s):  
Bladder Cancer ◽  
Urothelial Cancer ◽  
Clinical Investigation ◽  
Good Prognosis ◽  
New Drugs ◽  
Urothelial Bladder Cancer ◽  
Urothelial Bladder ◽  
Molecular Patterns ◽  
The Impact

Although bladder cancer is considered a chemosensitive malignancy, the prognosis of patients with metastatic disease is poor, with a median survival of approximately 12–14 months in good prognosis patients and with cure in only a minority. The addition of new drugs to the standard cisplatin-based regimens has not improved these outcomes. In this chapter, we highlight the role of chemotherapy and the impact of the new targeted agents in the treatment of metastatic bladder carcinoma. A better understanding of the underlying biology and the molecular patterns of urothelial bladder cancer has led to clinical investigation of several therapeutic targets. To date, these agents have yet to demonstrate an improvement in overall survival. Urothelial cancer is extremely sensitive to checkpoint inhibition with both anti PD-1 and anti PDL1 antibodies. The future seems brighter with the advent of these new therapies.

Erdafitinib: A novel therapy for FGFR-mutated urothelial cancer

2020 ◽  
Vol 77 (5) ◽  
pp. 346-351 ◽  
Author(s):  
Kiera Roubal ◽  
Zin W Myint ◽  
Jill M Kolesar
Keyword(s):  
Bladder Cancer ◽  
Urothelial Cancer ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Clinical Effectiveness ◽  
Genetic Alterations ◽  
Novel Therapy ◽  
Days Of Therapy ◽  
Phase 2 Clinical Trial ◽  
Gene Alterations

Abstract Purpose To provide an overview of fibroblast growth factor receptor (FGFR) gene alterations and the pharmacology, clinical effectiveness, dosage and administration, cost, and place in therapy of erdafitinib in bladder cancer. Summary Erdafitinib (Balversa, Janssen Pharmaceuticals) is a novel pan-FGFR inhibitor recently approved for the treatment of patients with advanced urothelial cancer with specific FGFR genetic alterations who have received at least one prior platinum-containing regimen. Erdafitinib binding to the FGFR2 and FGFR3 receptors inhibits FGF activity, resulting in cell death. Erdafitinib is available in tablet form, and the current recommended daily dosing is 8 mg, with dose escalation to 9 mg after 14 to 21 days of therapy if tolerated. A phase 2 clinical trial demonstrated that patients who received erdafitinib experienced on average 5.5 months of progression-free survival (95% confidence interval [CI], 4.2-6.0 months). In addition, 40% (95% CI, 31-50%) of patients responded to erdafitinib therapy. Patients receiving erdafitinib therapy should be monitored specifically for elevations in serum phosphate levels and changes in vision. Other adverse effects include anemia, thrombocytopenia, and electrolyte abnormalities. Conclusion Erdafitinib is the first small-molecule FGFR inhibitor approved for use in advanced bladder cancer.

scholarly journals Can CT Virtual Cystoscopy Replace Conventional Cystoscopy in Early Detection of Bladder Cancer?

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Sachin Abrol ◽  
Ankush Jairath ◽  
Sanika Ganpule ◽  
Arvind Ganpule ◽  
Shashikant Mishra ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Early Detection ◽  
Predictive Value ◽  
Bladder Tumor ◽  
Urothelial Cancer ◽  
Routine Clinical Practice ◽  
Bladder Tumors ◽  
Virtual Cystoscopy ◽  
Sensitivity Specificity

Aim. To correlate findings of conventional cystoscopy with CT virtual cystoscopy (CTVC) in detecting bladder tumors and to evaluate accuracy of virtual cystoscopy in early detection of bladder cancer.Material and Method. From June 2013 to June 2014, 50 patients (46 males, four females) with history and investigations suggestive of urothelial cancer, with mean age 62.76 ± 10.45 years, underwent CTVC by a radiologist as per protocol and subsequently underwent conventional cystoscopy (CPE) the same day or the next day. One urologist and one radiologist, blinded to the findings of conventional cystoscopy, independently interpreted the images, and any discrepant readings were resolved with consensus.Result. CTVC detected 23 out of 25 patients with bladder tumor(s) correctly. Two patients were falsely detected as negative while two were falsely labeled as positive in CTVC. Virtual and conventional cystoscopy were comparable in detection of tumor growth in urinary bladder. The sensitivity, specificity, positive predictive value, and negative predictive value of virtual cystoscopy were 92% each.Conclusion. CTVC correlates closely with the findings of conventional cystoscopy. Bladder should be adequately distended and devoid of urine at the time of procedure. However, more studies are required to define the role of virtual cystoscopy in routine clinical practice.

Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO): A single-arm, open-label window-of-opportunity trial of neoadjuvant abemaciclib in platinum-ineligible muscle invasive bladder cancer patients.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS606-TPS606
Author(s):  
Jones Nauseef ◽  
Panagiotis J. Vlachostergios ◽  
Ana M. Molina ◽  
David M. Nanus ◽  
Cora N. Sternberg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Clinical Trial ◽  
Bladder Cancer ◽  
Neoadjuvant Therapy ◽  
Urothelial Cancer ◽  
Window Of Opportunity ◽  
Muscle Invasive Bladder Cancer ◽  
Cell Cycle Genes ◽  
Cell Cycle Inhibition ◽  
Muscle Invasive

TPS606 Background: The standard of care for clinically localized muscle-invasive bladder cancer (MIBC) is neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy (RC). Up to 40% of patients (pts) are ineligible to receive cisplatin and proceed to RC without any neoadjuvant therapy. We and others have demonstrated enrichment of molecular alterations in cell cycle genes in MIBC, including copy number losses of CDKN2A in 41% of pts. Abemaciclib is a unique CDK4/6 inhibitor with single agent activity and a target kinome distinct from other CDK4/6 inhibitors. We have demonstrated that CRISPR knockout of CDKN2A increases susceptibility to abemaciclib in bladder cancer cell lines. Beyond tumor-intrinsic effects, abemaciclib also modulates the tumor microenvironment (TME) via upregulating human endogenous retroviral elements and increasing T cell infiltration. Methods: Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO) is a single arm, window-of-opportunity trial of neoadjuvant abemaciclib which will evaluate tumor cell and TME changes in response to abemaciclib. Enrolled pts must be ineligible for platinum-based neoadjuvant therapy for resectable MIBC. Pts receive abemaciclib (200 mg BID PO) for 4 weeks prior to RC. Tumor tissue collected via transurethral resection of bladder tumor (TURBT) and residual tumor at RC undergo single cell RNA sequencing and whole-exome sequencing. Patient-derived organoids and xenografts are generated for a co-clinical trial of abemaciclib alone or in combination. The primary endpoint is the measurement of changes in cell cycle dynamics. Secondary objectives are assessment of toxicity via NCI CTCAE v 5.0 and pathologic downstaging of MIBC. We will perform targeted sequencing of a panel of cell cycle genes in serial plasma and urine cell free DNA to evaluate changes in the variant allele fractions of somatic alterations. The novel design of this trial allows dynamic in vivo assessment of tumor changes and creates a new paradigm for studying tumor evolution in real time. Clinical trial information: NCT03837821.

Sign in / Sign up

Export Citation Format

Share Document