scholarly journals Fascin Inhibitors Decrease Cell Migration and Adhesion While Increase Overall Survival of Mice Bearing Bladder Cancers

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2698
Author(s):  
Zhankui Zhao ◽  
Yufeng Wang ◽  
J. Jillian Zhang ◽  
Xin-Yun Huang
Keyword(s):  
Overall Survival ◽  
Bladder Cancer ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Early Stage ◽  
Primary Tumor Growth ◽  
Bladder Tumors ◽  
Bladder Cancer Cells ◽  
New Treatment ◽  
New Treatments

Bladder cancer is one of the most common cancers in the world. Early stage bladder tumors can be surgically removed, but these patients usually have relapses. When bladder cancer becomes metastatic, survival is very low. There is an urgent need for new treatments for metastatic bladder cancers. Here, we report that a new fascin inhibitor decreases the migration and adhesion of bladder cancer cells. Furthermore, this inhibitor decreases the primary tumor growth and increases the overall survival of mice bearing bladder cancers, alone, as well as in combination with the chemotherapy medication, cisplatin, or the immune checkpoint inhibitor, anti-PD-1 antibody. These data suggest that fascin inhibitors can be explored as a new treatment for bladder cancers.

scholarly journals Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Junyu Long ◽  
Dongxu Wang ◽  
Xu Yang ◽  
Anqiang Wang ◽  
Yu Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bladder Cancer ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Esophagogastric Cancer ◽  
Clinical Benefits

Abstract Background Immune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy. Methods We tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data. Results We collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets. Conclusions Our findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.

scholarly journals Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer

Medicina ◽  
2021 ◽  
Vol 57 (8) ◽  
pp. 769
Author(s):  
Arthur Peyrottes ◽  
Idir Ouzaid ◽  
Gianluigi Califano ◽  
Jean-Francois Hermieu ◽  
Evanguelos Xylinas
Keyword(s):  
Bladder Cancer ◽  
Clinical Trials ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Response Rate ◽  
Checkpoint Inhibitor ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Neoadjuvant Immunotherapy ◽  
Muscle Invasive

Background and Objectives: Facing neoadjuvant chemotherapy followed by surgery, neoadjuvant immunotherapy is an innovative concept in localized muscle-invasive bladder cancer. Herein, we performed a review of the available and ongoing evidence supporting immune checkpoint inhibitor (ICI) administration in the early stages of bladder cancer treatment. Materials and Methods: A literature search was performed on Medline and clinical trials databases, using the terms: “bladder cancer” OR “urothelial carcinoma”, AND “neoadjuvant immunotherapy” OR “preoperative immunotherapy”. We restricted our investigations to prospective clinical trials evaluating anti-PD-(L)1 and anti-CTLA-4 monoclonal antibodies. Data on efficacy, toxicity and potential biomarkers of response were retrieved. Results: The search identified 6 ICIs that were tested in the neoadjuvant setting for localized bladder cancer—4 anti-PD-(L)1 inhibitors (Pembrolizumab, Atezolizumab, Nivolumab and Durvalumab) and 2 anti-CTLA-4 inhibitors (Ipilimumab and Tremelimumab). Most of the existing literature was based on single-arm phase 2 clinical trials that included from 23 to 143 patients. The pathological complete response rate (pCR) and pathological response rate (pRR) ranged from 31% to 46% and from 55.9% to 66%, respectively. Survival data were immature at this time. The safety profile was acceptable, with severe treatment-related adverse events ranging from 6% to 41%. Conclusions: The results of early phase trials are encouraging, and more investigations are needed to strengthen the rationale for immune checkpoint inhibitor administration in localized muscle-invasive bladder cancer.

scholarly journals Targeting S1PR1 May Result in Enhanced Migration of Cancer Cells in Bladder Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4474
Author(s):  
Chin-Li Chen ◽  
En Meng ◽  
Sheng-Tang Wu ◽  
Hsing-Fan Lai ◽  
Yi-Shan Lu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Immune Cell ◽  
Underlying Mechanism ◽  
Relative Distribution ◽  
Bladder Tumors ◽  
Normal Tissues ◽  
Clinical Databases ◽  
Bladder Cancer Cells ◽  
Patient Prognosis

Clinical bladder tumor histological analysis shows that high expression of S1PR1 is associated with poor patient prognosis. However, there are no studies that describe the underlying mechanism. To investigate the relative distribution and actual function of S1PR1 in bladder tumors, we analyzed multiple clinical databases in combination with tumor purity and immune cell infiltration simulations, as well as databases of well-defined histological phenotypes of bladder cancer, and single-cell sequencing of adjacent normal tissues and bladder tumors, and further compared them with bladder cancer cell lines. The results showed that S1PR1 expression was generally higher in normal tissues than in bladder cancer tissues, and its distribution was mainly in endothelial cells or immune cells. The association between high S1PR1 expression and poor prognosis may be due to tumor invasion of adjacent normal tissues, where highly expressed S1PR1 may affect prognostic interpretation. The effect of S1PR1 itself on cancer cells was associated with cell adhesion, and in bladder cancer cells, S1PR1 expression was negatively correlated with cell motility. Moreover, the use of FTY-720 will cause an increased metastatic ability of bladder cancer cells. In conclusion, we suggest that the use of S1PR1-specific inhibition as a synergistic treatment requires more observation and consideration.

Defining Molecular Profiles of Poor Outcome in Patients With Invasive Bladder Cancer Using Oligonucleotide Microarrays

2006 ◽  
Vol 24 (5) ◽  
pp. 778-789 ◽  
Author(s):  
Marta Sanchez-Carbayo ◽  
Nicholas D. Socci ◽  
Juanjo Lozano ◽  
Fabien Saint ◽  
Carlos Cordon-Cardo
Keyword(s):  
Overall Survival ◽  
Bladder Cancer ◽  
Clinical Outcome ◽  
Tumor Staging ◽  
Invasive Disease ◽  
Bladder Tumors ◽  
Tissue Arrays ◽  
Node Metastases ◽  
Normal Urothelium ◽  
Immunohistochemical Analyses

Purpose Bladder cancer is a common malignancy characterized by a poor clinical outcome when tumors progress into invasive disease. We sought to define genetic signatures characteristic of aggressive clinical behavior in advanced bladder tumors. Methods Oligonucleotide arrays were utilized to analyze the transcript profiles of 105 bladder tumors: 33 superficial, 72 invasive lesions, and 52 normal urothelium. Hierarchical clustering and supervised algorithms were used to classify and stratify bladder tumors on the basis of stage, node metastases, and overall survival. Immunohistochemical analyses on bladder cancer tissue arrays (n = 294 cases) served to validate associations between marker expression, staging and outcome. Results Hierarchical clustering classified normal urothelium, superficial, and invasive tumors with 82.2% accuracy, and stratified bladder tumors on the basis of clinical outcome. Predictive algorithms rendered an 89%-correct rate for tumor staging using genes differentially expressed between superficial and invasive tumors. Accuracies of 82% and 90% were obtained for predicting overall survival when considering all patients with bladder cancer or only patients with invasive disease, respectively. A genetic profile consisting of 174 probes was identified in those patients with positive lymph nodes and poor survival. Two independent Global Test runs confirmed the robust association of this profile with lymph node metastases (P = 7.3–13) and overall survival (P = 1.9–14) simultaneously. Immunohistochemical analyses on tissue arrays sustained the significant association of synuclein with tumor staging and clinical outcome (P = .002). Conclusion Gene profiling provides a genomic-based classification scheme of diagnostic and prognostic utility for stratifying advanced bladder cancer. Identification of this poor outcome profile could assist in selecting patients who may benefit from more aggressive therapeutic intervention.

scholarly journals Analysis of Tumor Microenvironment Characteristics in Bladder Cancer: Implications for Immune Checkpoint Inhibitor Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xingyu Chen ◽  
Haotian Chen ◽  
Dong He ◽  
Yaxin Cheng ◽  
Yuxing Zhu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Checkpoint Inhibitor ◽  
Clinical Prognosis

The tumor microenvironment (TME) plays a crucial role in cancer progression and recent evidence has clarified its clinical significance in predicting outcomes and efficacy. However, there are no studies on the systematic analysis of TME characteristics in bladder cancer. In this study, we comprehensively evaluated the TME invasion pattern of bladder cancer in 1,889 patients, defined three different TME phenotypes, and found that different subtypes were associated with the clinical prognosis and pathological characteristics of bladder cancer. We further explored the signaling pathways, cancer-immunity cycle, copy number, and somatic mutation differences among the different subtypes and used the principal component analysis algorithm to calculate the immune cell (IC) score, a tool for comprehensive evaluation of TME. Univariate and multivariate Cox regression analyses showed that ICscore is a reliable and independent prognostic biomarker. In addition, the use of anti-programmed death-ligand (PD-L1) treatment cohort, receiver operating characteristic (ROC) curve, Tumor Immune Dysfunction and Exclusion (TIDE), Subnetwork Mappings in Alignment of Pathways (SubMAP), and other algorithms confirmed that ICscore is a reliable prognostic biomarker for immune checkpoint inhibitor response. Patients with higher ICscore showed a significant therapeutic advantage in immunotherapy. In conclusion, this study improves our understanding of the characteristics of TME infiltration in bladder cancer and provides guidance for more effective personalized immunotherapy strategies.

scholarly journals Positive Programmed Cell Death-Ligand 1 Expression Predicts Poor Treatment Outcomes in Esophageal Squamous Cell Carcinoma Patients Receiving Neoadjuvant Chemoradiotherapy

2019 ◽  
Vol 8 (11) ◽  
pp. 1864 ◽  
Author(s):  
Huang ◽  
Lu ◽  
Wang ◽  
Chen ◽  
Lo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Neoadjuvant Chemoradiotherapy ◽  
Disease Free Survival ◽  
Complete Response ◽  
Hazard Ratio ◽  
Free Survival ◽  
Disease Free

Background: Programmed cell death-ligand 1 (PD-L1) is present in a subgroup of cancer patients who may be favorable targets for immune checkpoint inhibitor therapies. However, the significance of the PD-L1 expression in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy remains unclear. Methods: By means of PD-L1 immunohistochemistry 22C3 pharmDx assay, we evaluate the PD-L1 expression and its association with clinical outcome in 107 ESCC patients receiving neoadjuvant chemoradiotherapy. Results: Patients with positive PD-L1 expression have significantly lower pathological complete response rates (13% versus 32%; P = 0.036) than those with negative PD-L1 expression. Univariate survival analysis found that positive PD-L1 expression were correlated with poor overall survival (P = 0.004) and inferior disease-free survival (P < 0.001). In a multivariate analysis, positive PD-L1 expression was independently associated with the absence of a pathologically complete response (P = 0.044, hazard ratio: 3.542), worse overall survival (P = 0.006, hazard ratio: 2.017), and inferior disease-free survival (P < 0.001, hazard ratio: 2.516). Conclusions: For patients with ESCC receiving neoadjuvant chemoradiotherapy, positive PD-L1 expression independently predicts the poor chemoradiotherapy response and worse treatment outcome. Thus, our data suggests that PD-L1 may be an influential biomarker for prognostic classification and for immune checkpoint inhibitor therapies in ESCC patients receiving neoadjuvant chemoradiotherapy.

Use of a MET-specific photoprobe to identify bladder tumors in an orthotopic xenograft model of bladder cancer.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 260-260
Author(s):  
M. Sorbellini ◽  
A. Giubellino ◽  
G. Srivastava ◽  
C. Sourbier ◽  
E. Jagoda ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Optical Imaging ◽  
Transitional Cell ◽  
Xenograft Model ◽  
Bladder Tumors ◽  
Orthotopic Xenograft ◽  
Orthotopic Xenograft Model ◽  
Normal Bladder ◽  
Bladder Cancer Cells ◽  
Before And After

260 Background: Met over-expression has been found in bladder cancer (CaB). Stage and grade increases in urothelial carcinoma have been found to correlate with increases in Met expression. To assess whether molecular optical imaging could enhance the detection of bladder tumors, we used a Met-specific soluble photoprobe in an orthotopic xenograft model of bladder transitional cell carcinoma (TCC). Methods: An orthotopic xenograft murine model of CaB was developed with T24-Luciferase-positive bladder cancer cells. Presence of tumor was confirmed by luciferase optical imaging (Xenogen IVIS) of mice, 4 weeks after TCC cell implantation. Mice were euthanized and their bladders removed and bivalved. Bladders were incubated for 30 minutes with unbound fluorophore (Cy5**, Peak emission at 675 nM) and subsequently for another 30 minutes with Cy5** bound to a Met-specific peptide. Fluorescence imaging (Maestro) was performed before and after each incubation period. Following imaging, presence of tumor was confirmed histologically. Results: Cy5**-Met- peptide bound in sufficient density to tumor tissue in bladders for visualization by optical imaging. The tumor to normal bladder imaging ratio ranged from 2:1 to 8:1. Bladder regions with high uptake of Cy5**-Met-peptide corresponded to tumor areas confirmed by histological analysis. Conclusions: Cy5**-Met-peptide successfully targets Met in an orthotopic xenograft model of bladder cancer. Our results suggest that this agent maybe useful for the enhanced visualization of bladder cancer tumors during cystoscopy. No significant financial relationships to disclose.

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