scholarly journals Pparg drives luminal differentiation and luminal tumor formation in the urothelium

2021 ◽  
Author(s):  
Tiffany Tate ◽  
Tina Xiang ◽  
Mi Zhou ◽  
William Y. Kim ◽  
Xiao Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Nuclear Receptor ◽  
Tumor Formation ◽  
The Body ◽  
Luminal Subtype ◽  
Basal Subtype ◽  
Luminal Tumor ◽  
Muscle Invasive ◽  
Treatment And Diagnosis

AbstractPparg, a nuclear receptor, is downregulated in basal subtype bladder cancers that tend to be muscle invasive and amplified in luminal subtype bladder cancers that tend to be non-muscle invasive. Bladder cancers derive from the urothelium, one of the most quiescent epithelia in the body which is composed of basal, intermediate, and superficial cells. We find that expression of an activated form of Pparg (VP16;Pparg) in basal progenitors induces formation of superficial cells in situ, that exit the cell cycle, and do not form tumors. Expression in basal progenitors that have been activated by mild injury however, results in luminal tumor formation. We find that tumors are immune deserted, which may be linked to downregulation of Nf-kb, a Pparg target. Interestingly, some luminal tumors begin to shift to basal subtype tumors with time, downregulating Pparg and other luminal markers. Our findings have important implications for treatment and diagnosis bladder cancer.

scholarly journals Complications of intravesical BCG therapy in non-muscle invasive bladder cancer: our tertiary care centre experience

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Vivek Sharma ◽  
Avinash P. S. Thakur ◽  
Vasantharaja Ramasamy ◽  
Pushpendra Kumar Shukla ◽  
Fanindra Singh Solanki ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Adverse Effects ◽  
Bladder Carcinoma ◽  
Bladder Tumour ◽  
The Body ◽  
Bcg Therapy ◽  
Intravesical Bcg ◽  
Urothelial Bladder ◽  
Muscle Invasive ◽  
Intravesical Bcg Therapy

Abstract Background Urothelial bladder carcinoma accounts for around 3.9% cases of all the male cancers in India. Non-muscle-invasive bladder carcinoma (NMIBC) is predominant group which constitute approximately three fourth of the urothelial bladder cancer. Intravesical BCG immunotherapy is the corner stone of today’s NMIBC management. However, as with any other therapy it has its own complications and its interruption due to these adverse effects is a major cause of suboptimal efficacy. The aim of this study was to assess the complications of intravesical BCG therapy and their management in NMIBC patients. Methods This was a retrospective descriptive study conducted between October 2016 and November 2019; a backward review of 149 patients with diagnosis of NMIBC that undergone intravesicle BCG therapy was performed. Patient’s demographical, clinical, diagnostic and procedural data regarding bladder tumour, BCG therapy, its complications and management were collected and analysed. Results Total 149 patients were analysed, comprising 116 males and 33 females. The mean age was of 57.2 ± 6.7 years. Total 85.23% were primary and 14.76% were recurrent tumours. Total 96 patients (64.42%) completed the planned course, while 53 (35.57%) interrupted. The reasons for BCG interruption includes adverse effects (15.4%), progression of disease (6.7%), disease refractory to BCG (4.6%) and disease recurrence during BCG (3.3%). Most of the adverse events occurred in first 6 months and most interruptions occurred after the induction period. Cystitis was the most common observed adverse effect seen in 39.6% patients. Frequency, urgency, haematuria were common presentation. Radical cystectomy was the most common (16.10%) further treatment with patients whose treatment was interrupted. Conclusion BCG is an indispensable therapy available for NMIBC, but it is associated with array of adverse effects and complications, which are the main reasons for poor compliance to BCG therapy. Although BCG-related complications can affect any organ in the body, potentially life-threatening systemic BCG-related infections are encountered in only < 5% of patients. There are some difficulties in diagnosis of the BCG complications because acid-fast staining, culture and PCR test are not always positive; tissue biopsies should be indicated sometimes to evaluate histopathology and presence of M. bovis. A persistently monitored multidisciplinary approach with high index of suspicion and prompt anti-TB therapy can help to derive the maximum benefits while keeping the complications at check.

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.

Cell-cycle markers do not improve discrimination of EORTC and CUETO risk models in predicting recurrence and progression of non–muscle-invasive high-grade bladder cancer

2016 ◽  
Vol 34 (11) ◽  
pp. 485.e7-485.e14 ◽  
Author(s):  
Niccolo Passoni ◽  
Bishoy Gayed ◽  
Payal Kapur ◽  
Arthur I. Sagalowsky ◽  
Shahrokh F. Shariat ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
High Grade ◽  
Risk Models ◽  
Muscle Invasive

Subclonal mutational heterogeneity and survival in cisplatin-resistant muscle-invasive bladder cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4512-4512
Author(s):  
David Liu ◽  
Philip Abbosh ◽  
Daniel Keliher ◽  
Brendan Reardon ◽  
Kent William Mouw ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Overall Survival ◽  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Intratumoral Heterogeneity ◽  
Post Treatment ◽  
Cox Proportional Hazards Model ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

4512 Background: Biomarkers of survival and resistance in chemotherapy-resistant muscle-invasive bladder cancer (MIBC) are not well-characterized, but may inform management in this setting. Methods: Matched pre- and post-neoadjuvant cisplatin-based chemotherapy (NAC) tumor samples were obtained from 30 MIBC patients with gross residual disease (≥ pT2) at cystectomy, followed by whole exome sequencing of these “trios” (pre- and post-NAC tumor with matched germline samples). Phylogenetic analysis of matched tumor samples was performed to identify subclones, their associated mutations, and the corresponding enrichment in post-treatment tumors. Intratumoral heterogeneity was assessed by the proportion of mutations that were subclonal; the number of inferred subclones; and associated with overall survival using a Cox Proportional Hazards model. Results: Increased proportion of subclonal mutations in post-treatment tumors was associated with worse overall survival (HRR 1.86 [95% CI 1.12-3.06], p = 0.02), whereas pre-treatment proportion of subclonal mutations was only borderline statistically significant (HRR 1.48 [95% CI 0.99-2.20], p = 0.052). The total number of inferred tumor subclones in pre- or post-treatment tumor (or both) was associated with overall survival (HRR 1.60 [95% CI 1.05-2.43], p = 0.03), interpreted as a 60% increase in death rate per additional inferred subclone. While no single gene was statistically significantly enriched for new alterations in the post-chemotherapy resistant samples, we observed new post-treatment amplifications in cell-cycle genes ( E2F3, c-JUN), biallelic events in cell-cycle regulators ( FBXW7), and amplification of immune checkpoint genes ( PDL1/2). Conclusions: These results suggest that intratumoral heterogeneity (particularly post-therapy) predicts survival in a chemotherapy-resistant cohort. Further, alterations in cell cycle regulation may contribute to the mechanism of chemotherapy resistance. Finally, we observe evidence of immune checkpoint gene amplification post-treatment, suggesting that testing immune checkpoint blockade during NAC or, in high risk patients, following NAC may be warranted.

Evaluating cell cycle progression score as a prognostic marker for non-muscle invasive bladder cancer (NMIBC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 476-476
Author(s):  
Christopher J. Weight ◽  
Paari J Murugan ◽  
David Chesla ◽  
Resha Tejpaul ◽  
Ayman Soubra ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Prognostic Marker ◽  
Cell Cycle Progression ◽  
Multivariable Analysis ◽  
Invasive Bladder Cancer ◽  
Prognostic Information ◽  
Muscle Invasive Bladder Cancer ◽  
Cycle Progression ◽  
Muscle Invasive

476 Background: Accurate grading and staging from transurethral resection of bladder tumors (TURBT) is vital for appropriate clinical management. Non-muscle-invasive bladder cancer (NMIBC) can recur progress with higher grade and or stage progression to MIBC, requiring radical intervention with poorer prognosis. Further, grade and stage may change in 20-50% of TURBTs following re-review by expert GU pathologists Objective measures of stage and grade might offer additional and/or improved risk stratification; therefore we evaluated a molecular RNA signature as a prognostic marker for NMIBC. Methods: Patients were diagnosed with NMIBC at the University of Minnesota (UM)or Spectrum Health System(SHS) from 2005-2012. A Cell Cycle Progression (CCP) score was determined from the average expression of 36 CCP genes for patients with available FFPE diagnostic TURBT. The combined cohort consisted of 293 patients (UM n = 152, SHS n = 141). Study outcome was time from NMIBC diagnosis to progression to MIBC. Median follow-up for patients who did not experience an event was 4.4 years for UM and 6.9 for SHS. Association with outcomes was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests. All analyses were stratified by cohort. Results: CCP score was associated with progression to MIBC in univariable analysis [hazard ratio 1.42 (95% CI 1.19, 1.68), p = 4.3x10-5]. Tumor grade and stage were also highly prognostic. CCP score was strongly associated with stage (T1 vs Ta, p < 10-6) and grade (high vs low, p < 10-14) in both cohorts. As a result, CCP score did not provide independent prognostic information in multivariable analysis after adjusting for stage and grade (p = 0.32). There was a significant interaction between stage and CCP score (p = 0.0017), justifying an exploratory analysis of CCP score in Ta disease. In this subset, CCP score trended toward (p = 0.056) after adjusting for grade. Conclusions: In NMIBC, CCP score was highly correlated with tumor stage and grade and could serve as a quantitative measure of clinical parameters. The score may also provide prognostic information regarding risk of progression to MIBC, particularly in patients with Ta disease, but requires additional validation.

Mutational analysis using next-generation DNA sequencing in platinum-resistant muscle-invasive bladder cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16006-e16006
Author(s):  
Arash Samiei ◽  
Pritam Tayshetye ◽  
Angela Sanguino ◽  
Ralph Miller ◽  
John Lyne ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Dna Sequencing ◽  
Muscle Invasive Bladder Cancer ◽  
Molecular Alteration ◽  
Next Generation Dna Sequencing ◽  
Cell Cycle Pathway ◽  
Muscle Invasive ◽  
Molecular Landscape ◽  
Telomere Regulation

e16006 Background: Platinum-resistant muscle-invasive bladder cancer (prMIBC) is the main cause of bladder cancer mortality. Recent advances in next-generation DNA sequencing (NGS) has allowed characterization of the molecular landscape of MIBC. Yet, the correlation between the molecular alteration and the poor outcome of prMIBC is still lacking. This study aims to explore the potential genetic alterations in this group of patients. Methods: A retrospective study of prMIBC patients that had NGS molecular profiling at a single center from November 2014 to October 2018 was conducted. The prMIBC was defined as patients who had a significant residual disease or disease progression following cisplatin-based chemotherapy in a neoadjuvant or metastatic disease setting. NGS was performed on formalin-fixed paraffin-embedded tissue samples through commercial companies. Results: A total of 17 prMIBC with the median age of 65 [51-74] years old were included in this study. At the end of the study, 8 patients were alive and 9 deceased. A total of 58 mutations were identified. 7 of the 58 genes were mutated in ≥20% of cases: TP53 (65%), TERT promoter -124C > T (59%), ARID1A (35%), CDKN2A/B (30%), RB1 (24%), PIK3CA (24%), and FLCN (20%). Less frequent mutations (12% each) include MDM2, AKT2, KDM6A, SMARCA4, FGF3, FGF4, BRCA2, STAG2, and CCNE1 genes. Analysis of the mutations revealed key pathways including TP53/cell cycle pathway altered in 82%, PI-3K/mTOR pathway in 71%, Telomere regulation in 59%, SWI/SNF complex in 35% and histone modification in 24% of cases. Conclusions: Among patients with prMIBC, mutations in the p53/cell cycle pathway are the most common findings. Genetic alteration involving the PI-3K/mTOR pathway is frequently associated with prMIBC, which could provide an important lead for a predictive model and targeted intervention. Interestingly, the TERT promoter -124C > T mutation is a very common molecular alteration in prMIBC that has not been reported before. Telomere regulation may play a role in contributing to platinum-resistance in bladder cancer. Further elucidation of the molecular landscape in prMIBC on a larger scale would help to establish a molecular model to predict platinum-response in MIBC.

scholarly journals Obatoclax, a BH3 Mimetic, Enhances Cisplatin-Induced Apoptosis and Decreases the Clonogenicity of Muscle Invasive Bladder Cancer Cells via Mechanisms That Involve the Inhibition of Pro-Survival Molecules as Well as Cell Cycle Regulators

2019 ◽  
Vol 20 (6) ◽  
pp. 1285 ◽  
Author(s):  
Thomas Steele ◽  
George Talbott ◽  
Anhao Sam ◽  
Clifford Tepper ◽  
Paramita Ghosh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Bladder Cancer ◽  
Invasive Bladder Cancer ◽  
Dependent Manner ◽  
Cell Cycle Regulators ◽  
Muscle Invasive Bladder Cancer ◽  
Expression Levels ◽  
Muscle Invasive ◽  
Bh3 Mimetic

Several studies by our group and others have determined that expression levels of Bcl-2 and/or Bcl-xL, pro-survival molecules which are associated with chemoresistance, are elevated in patients with muscle invasive bladder cancer (MI-BC). The goal of this study was to determine whether combining Obatoclax, a BH3 mimetic which inhibits pro-survival Bcl-2 family members, can improve responses to cisplatin chemotherapy, the standard of care treatment for MI-BC. Three MI-BC cell lines (T24, TCCSuP, 5637) were treated with Obatoclax alone or in combination with cisplatin and/or pre-miR-34a, a molecule which we have previously shown to inhibit MI-BC cell proliferation via decreasing Cdk6 expression. Proliferation, clonogenic, and apoptosis assays confirmed that Obatoclax can decrease cell proliferation and promote apoptosis in a dose-dependent manner. Combination treatment experiments identified Obatoclax + cisplatin as the most effective treatment. Immunoprecipitation and Western analyses indicate that, in addition to being able to inhibit Bcl-2 and Bcl-xL, Obatoclax can also decrease cyclin D1 and Cdk4/6 expression levels. This has not previously been reported. The combined data demonstrate that Obatoclax can inhibit cell proliferation, promote apoptosis, and significantly enhance the effectiveness of cisplatin in MI-BC cells via mechanisms that likely involve the inhibition of both pro-survival molecules and cell cycle regulators.

Sign in / Sign up

Export Citation Format

Share Document