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Molecular Diagnostics and Therapeutic Target in Bladder Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 5881

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Special Issue Editor

Dr. Hideki Furuya

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Guest Editor

Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Interests: urinary biomarkers; early detection; prognostics; prediction of the response to treatment; bladder cancer; the role of sphingolipid signaling cascade in cancers
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Special Issue Information

Dear Colleagues,

Bladder cancer is the 6^th and 10^th most common cancer type in the US and worldwide, respectively. Bladder cancer represents one of the most challenging and expensive cancers to diagnose and treat because of its high recurrence rate. Most bladder cancers are diagnosed at an early stage, when they are highly treatable. However, about 25% of bladder cancers are diagnosed at later stages. When detected early (i.e., non-muscle invasive bladder cancer, NMIBC or stage 1), the 5-year survival rate is approximately 94%, compared to at best a 50% 5-year survival rate when the disease is noted to be muscle-invasive bladder cancer (MIBC, stage 2) and a less than 20% 5-year survival rate when the disease is metastatic (stages 3 and 4). Therefore, it is very important to detect bladder cancer at an early stage and to carefully monitor patients. However, currently bladder cancer diagnosis relies mainly on cystoscopy, an invasive and expensive procedure. Thus, there is an unmet need for non-invasive and accurate bladder cancer diagnosis techniques. In addition, many new drugs for bladder cancer have been introduced to clinical practice past several years, but they are mainly for the treatment of MIBC. The treatment for NMIBC still relies on transurethral resection followed by intravesical bacillus Calmette-Guerin (BCG). Thus, new therapeutics for NMIBC must be developed. Taken all together, this Special Issue is inviting research papers on molecular diagnostics and therapeutic target in bladder cancer, including but not limited to the biomarkers for early detection and progression, new therapeutic targets as well as first-in-class medications.

Dr. Hideki Furuya
Guest Editor

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Keywords

non-muscle invasive bladder cancer
muscle invasive bladder cancer
metastatic bladder cancer
diagnostic biomarkers
therapeutic targets

Published Papers (6 papers)

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Research

13 pages, 1781 KiB

Open AccessCommunication

Enhancing Therapeutic Efficacy and Safety of Immune Checkpoint Inhibition for Bladder Cancer: A Comparative Analysis of Injectable vs. Intravesical Administration

by Pradeep Tyagi, Jason Hafron, Jonathan Kaufman and Michael Chancellor

Int. J. Mol. Sci. 2024, 25(9), 4945; https://doi.org/10.3390/ijms25094945 - 01 May 2024

Viewed by 358

Abstract

Bladder cancer (BC) presents a significant global health burden, characterized by high recurrence rates post-initial treatment. Gender differences in BC prevalence and response to therapy emphasize the importance of personalized treatment strategies. While Bacillus Calmette–Guérin (BCG) remains a cornerstone of BC therapy, resistance poses a challenge, necessitating alternative strategies. Immune checkpoint inhibitors (ICIs) have shown promise, yet systemic toxicity raises concern. Intravesical administration of ICIs offers a potential solution, with recent studies demonstrating the feasibility and efficacy of intravesical pembrolizumab. Although systemic toxicity remains a concern, its localized administration may mitigate adverse events. Additionally, liposomal delivery of ICIs exhibits promises in enhancing drug penetration and reducing toxicity. Novel imaging modalities compatible with Vesical Imaging-Reporting and Data System (VI-RADS) and capable of predicting high-grade bladder cancer can aid the pre-operative shared decision making of patient and surgeon. Future research should focus on refining treatment approaches, optimizing dosing regimens, and leveraging advanced imaging techniques to improve patient outcomes. In conclusion, intravesical immunotherapy presents a promising avenue for BC treatment, offering enhanced therapeutic effectiveness while minimizing systemic toxicity. Continued research efforts are essential to validate these findings and optimize intravesical immunotherapy’s role in BC management, ultimately improving patient outcomes. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Therapeutic Target in Bladder Cancer)

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16 pages, 6382 KiB

Open AccessArticle

Change in Tissue Microbiome and Related Human Beta Defensin Levels Induced by Antibiotic Use in Bladder Carcinoma

by Ádám Monyók, Bassel Mansour, István Vadnay, Nóra Makra, Zsuzsanna A. Dunai, Éva Nemes-Nikodém, Balázs Stercz, Dóra Szabó and Eszter Ostorházi

Int. J. Mol. Sci. 2024, 25(8), 4562; https://doi.org/10.3390/ijms25084562 - 22 Apr 2024

Viewed by 341

Abstract

It is now generally accepted that the success of antitumor therapy can be impaired by concurrent antibiotic therapy, the presence of certain bacteria, and elevated defensin levels around the tumor tissue. The aim of our current investigation was to identify the underlying changes in microbiome and defensin levels in the tumor tissue induced by different antibiotics, as well as the duration of this modification. The microbiome of the tumor tissues was significantly different from that of healthy volunteers. Comparing only the tumor samples, no significant difference was confirmed between the untreated group and the group treated with antibiotics more than 3 months earlier. However, antibiotic treatment within 3 months of analysis resulted in a significantly modified microbiome composition. Irrespective of whether Fosfomycin, Fluoroquinolone or Beta-lactam treatment was used, the abundance of Bacteroides decreased, and Staphylococcus abundance increased. Large amounts of the genus Acinetobacter were observed in the Fluoroquinolone-treated group. Regardless of the antibiotic treatment, hBD1 expression of the tumor cells consistently doubled. The increase in hBD2 and hBD3 expression was the highest in the Beta-lactam treated group. Apparently, antibiotic treatment within 3 months of sample analysis induced microbiome changes and defensin expression levels, depending on the identity of the applied antibiotic. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Therapeutic Target in Bladder Cancer)

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17 pages, 1919 KiB

Open AccessArticle

Differential Expression of CKLF-like MARVEL Transmembrane Domain-Containing Protein 6 and Programmed Cell Death Ligand 1 as Prognostic Biomarkers in Upper Tract Urothelial Carcinoma

by Said Kdimati, Clemens Christoph, Änne Glass, Nadja Engel, Desiree-Louise Dräger, Claudia Maletzki, Anne-Sophie Becker and Annette Zimpfer

Int. J. Mol. Sci. 2024, 25(6), 3492; https://doi.org/10.3390/ijms25063492 - 20 Mar 2024

Viewed by 584

Abstract

Upper tract urothelial carcinoma (UTUC) accounts for 5–10% of all UCs. Immune checkpoint inhibitors (ICIs) have been established for UCs. The prognostic and predictive potential of programmed cell death ligand 1 (PD-L1) expression to stratify patients benefiting from ICIs is not fully understood, and additional markers influencing the impact of PD-L1-mediated ICI response are needed. Previously, the chemokine-like MARVEL transmembrane domain-containing protein 6 (CMTM6) was identified as a positive regulator of PD-L1. Our aim was to investigate the expression profiles and impact of PD-L1 and CMTM6 protein status on the prognostic parameters and survival of UTUC patients. In this retrospective study, the combined positive score (CPS), tumor proportion score (TPS), and immune cell score (ICS) for PD-L1 and CMTM6 were determined. High PD-L1 CPS, ICS, and TPS were found in 77.4%, 58.3%, and 45.2% of cases, and high CMTM6 CPS, ICS, and TPS were seen in 52.5%, 51.5%, and 55.5% of cases, respectively. The scores of both markers had a significant positive correlation. High PD-L1 and CMTM6 expression was coupled with higher pT status, WHO grade, necrosis, and metastasis (p < 0.05, respectively). In the univariate survival analysis, patients with a PD-L1 ICS high and higher degree of intratumoral inflammation showed significantly longer overall survival. Compared to other studies on UC, our study shows a substantially higher rate of PD-L1-positive tumors. CMTM6 was associated with more aggressive tumors. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Therapeutic Target in Bladder Cancer)

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15 pages, 4721 KiB

Open AccessArticle

MRI/RNA-Seq-Based Radiogenomics and Artificial Intelligence for More Accurate Staging of Muscle-Invasive Bladder Cancer

by Touseef Ahmad Qureshi, Xingyu Chen, Yibin Xie, Kaoru Murakami, Toru Sakatani, Yuki Kita, Takashi Kobayashi, Makito Miyake, Simon R. V. Knott, Debiao Li, Charles J. Rosser and Hideki Furuya

Int. J. Mol. Sci. 2024, 25(1), 88; https://doi.org/10.3390/ijms25010088 - 20 Dec 2023

Viewed by 1046

Abstract

Accurate staging of bladder cancer assists in identifying optimal treatment (e.g., transurethral resection vs. radical cystectomy vs. bladder preservation). However, currently, about one-third of patients are over-staged and one-third are under-staged. There is a pressing need for a more accurate staging modality to evaluate patients with bladder cancer to assist clinical decision-making. We hypothesize that MRI/RNA-seq-based radiogenomics and artificial intelligence can more accurately stage bladder cancer. A total of 40 magnetic resonance imaging (MRI) and matched formalin-fixed paraffin-embedded (FFPE) tissues were available for analysis. Twenty-eight (28) MRI and their matched FFPE tissues were available for training analysis, and 12 matched MRI and FFPE tissues were used for validation. FFPE samples were subjected to bulk RNA-seq, followed by bioinformatics analysis. In the radiomics, several hundred image-based features from bladder tumors in MRI were extracted and analyzed. Overall, the model obtained mean sensitivity, specificity, and accuracy of 94%, 88%, and 92%, respectively, in differentiating intra- vs. extra-bladder cancer. The proposed model demonstrated improvement in the three matrices by 17%, 33%, and 25% and 17%, 16%, and 17% as compared to the genetic- and radiomic-based models alone, respectively. The radiogenomics of bladder cancer provides insight into discriminative features capable of more accurately staging bladder cancer. Additional studies are underway. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Therapeutic Target in Bladder Cancer)

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32 pages, 7822 KiB

Open AccessArticle

OncoTherad^® (MRB-CFI-1) Nanoimmunotherapy: A Promising Strategy to Treat Bacillus Calmette–Guérin-Unresponsive Non-Muscle-Invasive Bladder Cancer: Crosstalk among T-Cell CX3CR1, Immune Checkpoints, and the Toll-Like Receptor 4 Signaling Pathway

by João Carlos Cardoso Alonso, Bianca Ribeiro de Souza, Ianny Brum Reis, Gabriela Cardoso de Arruda Camargo, Gabriela de Oliveira, Maria Izabel de Barros Frazão Salmazo, Juliana Mattoso Gonçalves, José Ronaldo de Castro Roston, Paulo Henrique Ferreira Caria, André da Silva Santos, Leandro Luiz Lopes de Freitas, Athanase Billis, Nelson Durán and Wagner José Fávaro

Int. J. Mol. Sci. 2023, 24(24), 17535; https://doi.org/10.3390/ijms242417535 - 15 Dec 2023

Viewed by 1853

Abstract

This study assessed the safety and efficacy of OncoTherad^® (MRB-CFI-1) nanoimmunotherapy for non-muscle invasive bladder cancer (NMIBC) patients unresponsive to Bacillus Calmette-Guérin (BCG) and explored its mechanisms of action in a bladder cancer microenvironment. A single-arm phase I/II study was conducted with 44 patients with NMIBC who were unresponsive to BCG treatment. Primary outcomes were pathological complete response (pCR) and relapse-free survival (RFS). Secondary outcomes comprised response duration and therapy safety. Patients’ mean age was 65 years; 59.1% of them were refractory, 31.8% relapsed, and 9.1% were intolerant to BCG. Moreover, the pCR rate after 24 months reached 72.7% (95% CI), whereas the mean RFS reached 21.4 months. Mean response duration in the pCR group was 14.3 months. No patient developed muscle-invasive or metastatic disease during treatment. Treatment-related adverse events occurred in 77.3% of patients, mostly grade 1–2 events. OncoTherad^® activated the innate immune system through toll-like receptor 4, leading to increased interferon signaling. This activation played a crucial role in activating CX3CR1⁺ CD8 T cells, decreasing immune checkpoint molecules, and reversing immunosuppression in the bladder microenvironment. OncoTherad^® has proved to be a safe and effective therapeutic option for patients with BCG-unresponsive NMIBC, besides showing likely advantages in tumor relapse prevention processes. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Therapeutic Target in Bladder Cancer)

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18 pages, 7241 KiB

Open AccessArticle

Elucidating the Associated Biological Function and Clinical Significance of RHOJ Expression in Urothelial Carcinoma

by Xin-Jie Lu, Hsing-Fan Lai, Sheng-Cheng Wu, Chin-Li Chen and Yi-Lin Chiu

Int. J. Mol. Sci. 2023, 24(18), 14081; https://doi.org/10.3390/ijms241814081 - 14 Sep 2023

Viewed by 1023

Abstract

Urothelial cancer, a common urinary system malignancy, often presents treatment challenges due to metastasis and chemotherapy side effects. Angiogenesis, crucial for tumor growth, has become a target for drug development. This study explores the expression, prognostic value, and clinical correlation of RHOJ in the TCGA BLCA, GSE31684, and GSE32894 datasets. We identify common differentially expressed genes across these databases and utilize g:Profiler and Cytoscape ClueGO for functional assessment. Further, we perform a gene set enrichment analysis (GSEA) using Hallmark gene sets and use the imsig package for immune cell infiltration analysis. Our analysis indicates that RHOJ expression levels significantly impact survival rates, tumor progression, and immune response in urothelial tumors. High RHOJ expression correlated with poor prognosis, advanced disease stages, and an increase in monocyte population within the tumor microenvironment. This aligns with current literature indicating a key role of immune infiltration in bladder cancer progression and treatment response. Moreover, the GSEA and imsig results further suggest a potential mechanistic link between RHOJ expression and immune-related pathways. Considering the increasing emphasis on immunotherapeutic strategies in bladder cancer management, our findings on RHOJ’s potential as a diagnostic biomarker and its association with immune response open new avenues for therapeutic interventions. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Therapeutic Target in Bladder Cancer)

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