FGFR3 Alterations in the Era of Immunotherapy for Urothelial Bladder Cancer

Kacew, Alec; Sweis, Randy F.

doi:10.3389/fimmu.2020.575258

Cited by 57 publications

(81 citation statements)

References 61 publications

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“…In patients who received previous ICI (n=22), the confirmed response rate was 59% [ 79 ]. Generally, patients with FGFR3 alterations exhibit lower responses to ICI, although FGFR3 alterations are correlated with a lower grade and stage of NMIBC and a favorable prognosis [ 80 ]. For these reasons, FGFR3 alterations are presumed to predict BCG responses.…”

Section: Emerging Therapies In Bcg-unresponsive Nmibcmentioning

confidence: 99%

Emerging treatments for bacillus Calmette–Guérin-unresponsive non-muscle-invasive bladder cancer

Kim

Seo

2021

Investig Clin Urol

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Intravesical bacillus Calmette–Guérin (BCG) immunotherapy has been the gold standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG immunotherapy prevents disease recurrence and progression to muscle-invasive disease following TURBT. Although most patients initially respond well to intravesical BCG, considerable concern has been raised for patients with BCG failure who are refractory or recur in 6 months after their last BCG, which implies ‘BCG-unresponsiveness’. Based on current clinical guidelines, early radical cystectomy (RC) is recommended to treat BCG-unresponsive NMIBC. However, due to the high risk of morbidity and mortality of RC and patients' desire to preserve their own bladder, there is a critical unmet need for alternative conservative treatments as bladder-sparing strategies in BCG-unresponsive patients. Trials for effective bladder-sparing treatments are ongoing, and several novel agents have been recently tested in the NMIBC setting. The goal of this review is to introduce and summarize recently reported novel and emerging drugs and ongoing clinical trials for BCG-unresponsive NMIBC.

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Section: Emerging Therapies In Bcg-unresponsive Nmibcmentioning

confidence: 99%

Emerging treatments for bacillus Calmette–Guérin-unresponsive non-muscle-invasive bladder cancer

Kim

Seo

2021

Investig Clin Urol

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“…The microenvironment of a tumor cell showing the dynamics of FGFR3 mutation on tumor cells (phosphorylation of the kinase region leads to activation of AKT, ERK, STAT, and MAPK proteins, which result in target DNA transcription leading to cell proliferation and cell survival), the activation of T cell by tumor cells, and suppression of T cell activation and proliferation by PD-L1 binding with PD-1 much-needed improvements in targeted therapeutics for bladder cancer. The rationale for combining FGFR3targeted therapy with immunotherapy is confirmed in preclinical and correlative literature and animal models suggest potential synergies between these two mechanisms [8]. When attempting to combine two very different therapeutic approaches that target distinct pathways, treatment outcomes can depend on the order and timing in which therapies are administered.…”

Section: Introductionmentioning

confidence: 99%

A validated mathematical model of FGFR3‐mediated tumor growth reveals pathways to harness the benefits of combination targeted therapy and immunotherapy in bladder cancer

et al. 2021

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Bladder cancer is a common malignancy with over 80,000 estimated new cases and nearly 18,000 deaths per year in the United States alone. Therapeutic options for metastatic bladder cancer had not evolved much for nearly four decades, until recently, when five immune checkpoint inhibitors were approved by the U.S. Food and Drug Administration (FDA). Despite the activity of these drugs in some patients, the objective response rate for each is less than 25%. At the same time, fibroblast growth factor receptors (FGFRs) have been attractive drug targets for a variety of cancers, and in 2019 the FDA approved the first therapy targeted against FGFR3 for bladder cancer. Given the excitement around these new receptor tyrosine kinase and immune checkpoint targeted strategies, and the challenges they each may face on their own, emerging data suggest that combining these treatment options could lead to improved therapeutic outcomes. In this paper, we develop a mathematical model for FGFR3‐mediated tumor growth and use it to investigate the impact of the combined administration of a small molecule inhibitor of FGFR3 and a monoclonal antibody against the PD‐1/PD‐L1 immune checkpoint. The model is carefully calibrated and validated with experimental data before survival benefits, and dosing schedules are explored. Predictions of the model suggest that FGFR3 mutation reduces the effectiveness of anti‐PD‐L1 therapy, that there are regions of parameter space where each monotherapy can outperform the other, and that pretreatment with anti‐PD‐L1 therapy always results in greater tumor reduction even when anti‐FGFR3 therapy is the more effective monotherapy.

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“…E2F7 contributes to both head and neck cancers and retinal cancers [ 34 ]. Another study found the expression of SNORD88C was similarly altered mRNA splicing for fibroblast growth factor receptor 3 (FGFR3) [ 35 ], which contributes to the progression of multiple cancer types [ 36 , 37 , 38 ]. Interestingly, this mechanism appeared to involve shorter derived sdRNAs from SNORD88C, and as it turns out, this may be a common way that snoRNA expand their influence.…”

Section: The Wider Biological Activities Of Snorna Extend Well Beyond the Ribosomementioning

confidence: 99%

SnoRNA in Cancer Progression, Metastasis and Immunotherapy Response

Werf

Chin

Fleming

2021

Biology

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Small nucleolar RNA (snoRNA) were one of our earliest recognised classes of non-coding RNA, but were largely ignored by cancer investigators due to an assumption that their activities were confined to the nucleolus. However, as full genome sequences have become available, many new snoRNA genes have been identified, and multiple studies have shown their functions to be diverse. The consensus now is that many snoRNA are dysregulated in cancers, are differentially expressed between cancer types, stages and metastases, and they can actively modify disease progression. In addition, the regulation of the snoRNA class is dominated by the cancer-supporting mTOR signalling pathway, and they may have particular significance to immune cell function and anti-tumour immune responses. Given the recent advent of therapeutics that can target RNA molecules, snoRNA have robust potential as drug targets, either solely or in the context of immunotherapies.

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FGFR3 Alterations in the Era of Immunotherapy for Urothelial Bladder Cancer

Cited by 57 publications

References 61 publications

Emerging treatments for bacillus Calmette–Guérin-unresponsive non-muscle-invasive bladder cancer

Emerging treatments for bacillus Calmette–Guérin-unresponsive non-muscle-invasive bladder cancer

A validated mathematical model of FGFR3‐mediated tumor growth reveals pathways to harness the benefits of combination targeted therapy and immunotherapy in bladder cancer

SnoRNA in Cancer Progression, Metastasis and Immunotherapy Response

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