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Cancers
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Targeted Therapy for Bladder Cancer
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Targeted Therapy for Bladder Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 18705

Special Issue Editor

Prof. Maximilian Burger

E-Mail Website
Guest Editor
Department of Urology, Caritas-St. Josef Medical Center, University of Regensburg, Germany
Interests: Uro-Oncology; robotical surgery; bladder cancer; prostate cancer; renal cell cancer; molecular markers; metastasis

Special Issue Information

Dear Colleagues,

This Special Issue is titled: “Targeted Therapy for bladder cancer” Why bladder cancer and why targeted therapy, though? Uro-oncology has improved massively over the past few years; surgery for localized disease has improved, and so has systemic medical therapy for metastatic disease. We have understood the great potential of local therapy in metastatic disease and the combination of local and systemic therapy in locally advanced disease; some old paradigms seem to have been overcome, too. These statements, however, are justified in prostate and renal cell caner more than in bladder cancer, where many unmet yet clinically pressing needs remain to be tackled: Can we expand bladder preservation in high-risk non-muscle-invasive stages? Can we improve overall outcome of local treatment for muscle-invasive stages by improving neo- and adjuvant medical therapy? Can we achieve long-term benefits for metastatic stages? Some of these questions may be answered by targeted therapy. Bladder cancer offers a variety of known targets; general mutational burden in bladder exceeds renal or prostate cancer; many molecular pathways are long known and offer therapeutical targets, some already in clinical application requiring use novel fields, some yet to come. Thus, unmet needs and targeted therapy may meet in bladder cancer. This Special Issue aims at original work and overviews adding to the current knowledge and showing potential future approaches of surgical and medical therapy aiming at predefined targets in non- and muscle-invasive, and locally advanced and metastatic stages.

Prof. Maximilian Burger
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • non-muscle-invasive bladder cancer
  • muscle-invasive bladder cancer
  • bladder preservation
  • neoadjuvant therapy
  • adjuvant therapy
  • metastatic disease

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Published Papers (5 papers)

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Research

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14 pages, 3649 KiB  
Article
Immunohistochemical Study of Bladder Cancer Molecular Subtypes and Their Association with PD-L1 Expression
by Dimitrios Goutas, Kostas Palamaris, Anastasios Stofas, Nektarios Politakis, Antonia Despotidi, Ioanna Giannopoulou, Nikolaos Goutas, Dimitrios Vlachodimitropoulos, Nikolaos Kavantzas, Andreas C. Lazaris and Hariklia Gakiopoulou
Cancers 2023, 15(1), 188; https://doi.org/10.3390/cancers15010188 - 28 Dec 2022
Cited by 6 | Viewed by 2794
Abstract
The significant heterogeneity in clinical outcomes among patients with bladder cancer has highlighted the existence of different biological subtypes of muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). Meanwhile, immune checkpoint proteins and their interference with tumor-related immune-evasive strategies has led to [...] Read more.
The significant heterogeneity in clinical outcomes among patients with bladder cancer has highlighted the existence of different biological subtypes of muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). Meanwhile, immune checkpoint proteins and their interference with tumor-related immune-evasive strategies has led to the development of several immunotherapeutic drugs targeting programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1). However, the lack of any known biomarker that could predict responses to immunotherapy has led to a more agnostic therapeutic approach. Here, we present a study conducted in 77 bladder cancer (BC) patients (n = 77), ranging from stages pTa to pT2. Tumor specimens were resected via transurethral resection of bladder tumor (TURBT) and consistuted of 24 low-grade (LG) and 53 high-grade (HG) tumors. Patients’ tumors were then categorized into molecular subtypes, via immunohistochemistry (CK5/6 and GATA3). Furthermore, all tumor specimens were stained with anti-PD-L1 and demonstrated significant correlations with basal immunophenotype, stage pT2 and HG tumors. As such, we attempted to stratify patients into groups of likely-responders and likely-not-responders to immunotherapy with anti-PD-L1, based on their molecular phenotype. Finally, in acknowledging the fact that there is a universal lack of biomarkers associated with predicting BC response to immunotherapeutic drugs, we tested all tumors for deficiency of mismatch repair proteins (MMR). Full article
(This article belongs to the Special Issue Targeted Therapy for Bladder Cancer)
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13 pages, 2264 KiB  
Article
Low CD8 T Cell Counts Predict Benefit from Hypoxia-Modifying Therapy in Muscle-Invasive Bladder Cancer
by Vicky Smith, Debayan Mukherjee, Anna Maria Tsakiroglou, Alexander Baker, Hitesh Mistry, Ananya Choudhury, Peter Hoskin, Timothy Illidge and Catharine M. L. West
Cancers 2023, 15(1), 41; https://doi.org/10.3390/cancers15010041 - 21 Dec 2022
Cited by 2 | Viewed by 2761
Abstract
Background: As hypoxia can drive an immunosuppressive tumour microenvironment and inhibit CD8+ T cells, we investigated if patients with low tumour CD8+ T cells benefitted from hypoxia-modifying therapy. Methods: BCON was a phase III trial that randomised patients with muscle-invasive bladder cancer (MIBC) [...] Read more.
Background: As hypoxia can drive an immunosuppressive tumour microenvironment and inhibit CD8+ T cells, we investigated if patients with low tumour CD8+ T cells benefitted from hypoxia-modifying therapy. Methods: BCON was a phase III trial that randomised patients with muscle-invasive bladder cancer (MIBC) to radiotherapy alone or with hypoxia-modifying carbogen plus nicotinamide (CON). Tissue microarrays of diagnostic biopsies from 116 BCON patients were stained using multiplex immunohistochemistry (IHC) with the markers CD8, CD4, FOXP3, CD68 and PD-L1, plus DAPI. Hypoxia was assessed using CA9 IHC (n = 111). Linked transcriptomic data (n = 80) identified molecular subtype. Relationships with overall survival (OS) were investigated using Cox proportional hazard models. Results: High (upper quartile) vs. low CD8 T cell counts associated with a better OS across the whole cohort at 16 years (n = 116; HR 0.47, 95% CI 0.28–0.78, p = 0.003) and also in the radiotherapy alone group (n = 61; HR 0.39, 95% CI 0.19–0.76, p = 0.005). Patients with low CD8+ T cells benefited from CON (n = 87; HR 0.63, 95% CI 0.4–1.0, p = 0.05), but those with high CD8 T cells did not (n = 27; p = 0.95). CA9 positive tumours had fewer CD8+ T cells (p = 0.03). Prognostic significance of low CD8+ T cells in the whole cohort remained after adjusting for clinicopathologic variables. Basal vs. luminal subtype had more CD8+ cells (p = 0.02) but was not prognostic (n = 80; p = 0.26). Exploratory analyses with other immune markers did not improve on findings obtained with CD8 counts. Conclusions: MIBC with low CD8+ T cell counts may benefit from hypoxia-modifying treatment. Full article
(This article belongs to the Special Issue Targeted Therapy for Bladder Cancer)
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Review

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13 pages, 617 KiB  
Review
Immune Predictors of Response after Bacillus Calmette–Guérin Treatment in Non-Muscle-Invasive Bladder Cancer
by Marta Rodríguez-Izquierdo, Carmen G. Del Cañizo, Carolina Rubio, Ignacio A. Reina, Mario Hernández Arroyo, Alfredo Rodríguez Antolín, Marta Dueñas Porto and Félix Guerrero-Ramos
Cancers 2023, 15(23), 5554; https://doi.org/10.3390/cancers15235554 - 23 Nov 2023
Cited by 3 | Viewed by 2002
Abstract
Bacillus Calmette–Guérin (BCG) has been the standard of care for the treatment of high-risk, non-muscle-invasive bladder cancer (NMIBC) for decades, but 49.6% of high-risk and very-high-risk patients will experience progression to muscle-invasive disease in five years. Furthermore, cytology and cystoscopy entail a high [...] Read more.
Bacillus Calmette–Guérin (BCG) has been the standard of care for the treatment of high-risk, non-muscle-invasive bladder cancer (NMIBC) for decades, but 49.6% of high-risk and very-high-risk patients will experience progression to muscle-invasive disease in five years. Furthermore, cytology and cystoscopy entail a high burden for both patients and health care systems due to the need for very long periods of follow-up. Subsequent adjuvant treatment using intravesical immunotherapy with BCG has been shown to be effective in reducing tumor recurrence and progression, but it is not free of severe adverse effects that ultimately diminish patients’ quality of life. Because not all patients benefit from BCG treatment, it is of paramount importance to be able to identify responders and non-responders to BCG as soon as possible in order to offer the best available treatment and prevent unnecessary adverse events. The tumor microenvironment (TME), local immune response, and systemic immune response (both adaptive and innate) seem to play an important role in defining responders, although the way they interact remains unclear. A shift towards a proinflammatory immune response in TME is thought to be related to BCG effectiveness. The aim of this review is to collect the most relevant data available regarding BCG’s mechanism of action, its role in modulating innate and adaptive immune responses and the secretion of certain cytokines, and their potential use as immunological markers of response; the aim is also to identify promising lines of investigation. Full article
(This article belongs to the Special Issue Targeted Therapy for Bladder Cancer)
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27 pages, 695 KiB  
Review
Current and Emerging Strategies to Treat Urothelial Carcinoma
by Berkha Rani, James J. Ignatz-Hoover, Priyanka S. Rana and James J. Driscoll
Cancers 2023, 15(19), 4886; https://doi.org/10.3390/cancers15194886 - 8 Oct 2023
Cited by 6 | Viewed by 3147
Abstract
Urothelial cell carcinoma (UCC, bladder cancer, BC) remains a difficult-to-treat malignancy with a rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age; it is ~four times more [...] Read more.
Urothelial cell carcinoma (UCC, bladder cancer, BC) remains a difficult-to-treat malignancy with a rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age; it is ~four times more commonly observed in men than women. The most important risk factor for developing BC is tobacco smoking, which accounts for ~50% of cases, followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC remains generally incurable and is associated with intrinsic and acquired drug and immune resistance. UCC is lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and a high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss therapies to improve UCC management and how comprehensive tumor profiling can identify actionable biomarkers and eventually fulfill the promise of precision medicine for UCC patients. Full article
(This article belongs to the Special Issue Targeted Therapy for Bladder Cancer)
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30 pages, 2042 KiB  
Review
Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy
by Marine M. Leblond, Hana Zdimerova, Emma Desponds and Grégory Verdeil
Cancers 2021, 13(18), 4712; https://doi.org/10.3390/cancers13184712 - 21 Sep 2021
Cited by 36 | Viewed by 6526
Abstract
Tumor-associated macrophages (TAMs) are one of the most abundant infiltrating immune cells of solid tumors. Despite their possible dual role, i.e., pro- or anti-tumoral, there is considerable evidence showing that the accumulation of TAMs promotes tumor progression rather than slowing it. Several strategies [...] Read more.
Tumor-associated macrophages (TAMs) are one of the most abundant infiltrating immune cells of solid tumors. Despite their possible dual role, i.e., pro- or anti-tumoral, there is considerable evidence showing that the accumulation of TAMs promotes tumor progression rather than slowing it. Several strategies are being developed and clinically tested to target these cells. Bladder cancer (BCa) is one of the most common cancers, and despite heavy treatments, including immune checkpoint inhibitors (ICIs), the overall patient survival for advanced BCa is still poor. TAMs are present in bladder tumors and play a significant role in BCa development. However, few investigations have analyzed the effect of targeting TAMs in BCa. In this review, we focus on the importance of TAMs in a cancerous bladder, their association with patient outcome and treatment efficiency as well as on how current BCa treatments impact these cells. We also report different strategies used in other cancer types to develop new immunotherapeutic strategies with the aim of improving BCa management through TAMs targeting. Full article
(This article belongs to the Special Issue Targeted Therapy for Bladder Cancer)
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