Advancing Patient-Centered Outcomes and Equity in Clinical Trials for BCG-Unresponsive Nonmuscle Invasive Bladder Cancer

Hwang, Thomas J.; Davies, Benjamin J.; Preston, Mark A.

doi:10.1001/jamaoncol.2023.3304

JAMA Oncol

2023

DOI: 10.1001/jamaoncol.2023.3304

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Advancing Patient-Centered Outcomes and Equity in Clinical Trials for BCG-Unresponsive Nonmuscle Invasive Bladder Cancer

Thomas J. Hwang,

Benjamin J. Davies,

Mark A. Preston

Abstract: This Viewpoint encourages investigators to move beyond FDA guidance toward patient-centered therapies and health equity for BCG-unresponsive bladder cancer.

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2024

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Cited by 2 publications

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Methionine-driven YTHDF1 expression facilitates bladder cancer progression by attenuating RIG-I-modulated immune responses and enhancing the eIF5B-PD-L1 axis

Yu,

Fu,

Jing

et al. 2024

Cell Death Differ

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The impact of amino acids on tumor immunotherapy is gradually being uncovered. In this study, we screened various essential and non-essential amino acids and found that methionine enhances mRNA methylation and reduced the activation of Type I interferon pathway in bladder cancer. Through RNA sequencing, point mutations, MB49 mouse tumor models, and single-cell RNA sequencing, we demonstrated that high methionine levels elevate the expression of m6A reader YTHDF1, promoting the degradation of RIG-I, thereby inhibiting the RIG-I/MAVS-mediated IFN-I pathway and reducing the efficacy of tumor immunotherapy. Additionally, immunoprecipitation and mass spectrometry revealed that YTHDF1 binds to the eukaryotic translation initiation factor eIF5B, which acts on PD-L1 mRNA to enhance its translation and promote immune evasion. By intravesical administration of oncolytic bacteria VNP20009, we effectively depleted methionine locally, significantly prolonging mouse survival and enhancing immune cell infiltration and differentiation within tumors. Multiplex immunofluorescence assays in bladder cancer immunotherapy patients confirmed our findings. Our research elucidates two mechanisms by which methionine inhibits bladder cancer immunotherapy and proposes a targeted methionine depletion strategy that advances research while minimizing nutritional impact on patients.

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Methionine-driven YTHDF1 expression facilitates bladder cancer progression by attenuating RIG-I-modulated immune responses and enhancing the eIF5B-PD-L1 axis

Yu,

Fu,

Jing

et al. 2024

Cell Death Differ

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Does radical cystectomy still have a role in BCG-unresponsive nonmuscle invasive bladder cancer?

Xia,

Daneshmand

2024

Current Opinion in Urology

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Purpose of review Several novel therapies approved by the Food and Drug Administration (FDA) and explosion of clinical trials have changed the landscape Bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle invasive bladder cancer (NMIBC). Given the recent advancements in bladder sparing options, the role of radical cystectomy (RC) in BCG-unresponsive NMIBC remains a subject of debate. Recent findings All three novel agents currently approved by the FDA for BCG-unresponsive NMIBC have strict indication [carcinoma in situ (CIS)], low response rate, and short response duration. Some promising new agents are awaiting results and/or FDA approval. RC still provides the best oncologic control and acceptable quality of life, and potentially represents the most cost-effective option. Summary It is an exciting time for the urologic oncology community to see the FDA approvals of some of the novel bladder sparing therapies and expansion of ongoing clinical trials. Yet, RC should still be considered as the gold standard of BCG-unresponsive NMIBC. We also must be cautious and selective in recommending bladder sparing options for patients with BCG-unresponsive NMIBC.

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Advancing Patient-Centered Outcomes and Equity in Clinical Trials for BCG-Unresponsive Nonmuscle Invasive Bladder Cancer

Abstract: This Viewpoint encourages investigators to move beyond FDA guidance toward patient-centered therapies and health equity for BCG-unresponsive bladder cancer.

Cited by 2 publications

References 6 publications

Methionine-driven YTHDF1 expression facilitates bladder cancer progression by attenuating RIG-I-modulated immune responses and enhancing the eIF5B-PD-L1 axis

Methionine-driven YTHDF1 expression facilitates bladder cancer progression by attenuating RIG-I-modulated immune responses and enhancing the eIF5B-PD-L1 axis

Does radical cystectomy still have a role in BCG-unresponsive nonmuscle invasive bladder cancer?

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