Novel therapies in urothelial carcinoma: a biomarker-driven approach

Iyer, Gopa; Rosenberg, Jonathan E.

doi:10.1093/annonc/mdy254

Cited by 11 publications

(7 citation statements)

References 75 publications

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“…Hence, there is an urgent need for significant progress in enhancing clinical management for these patients. Immunotherapy and targeted therapy with new agents directed at specific molecular pathways represent a promising avenue for achieving substantial progress [3]. Large‐scale collaborations utilizing next‐generation sequencing (NGS), such as The Cancer Genome Atlas (TCGA), have already contributed to our understanding of the molecular mechanisms underlying UrCa [4].…”

Section: Introductionmentioning

confidence: 99%

TP53 disruptive mutation predicts platinum‐based chemotherapy and PD‐1/PD‐L1 blockade response in urothelial carcinoma

Jin,

Xu,

et al. 2024

The Journal of Pathology

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TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co‐occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild‐type TP53. Significantly, patients with TP53Disruptive mutations exhibit an increased probability of responding favorably to PD‐1/PD‐L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53Disruptive mutations showed an enriched APOBEC‐ and POLE‐related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon‐gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD‐1/PD‐L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics‐guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Section: Introductionmentioning

confidence: 99%

TP53 disruptive mutation predicts platinum‐based chemotherapy and PD‐1/PD‐L1 blockade response in urothelial carcinoma

Jin,

Xu,

et al. 2024

The Journal of Pathology

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“…arylamines) are the primary risk factors for developing urothelial bladder cancer in the United States of America, and they also enhance the likelihood of recurrence ( 3 ). Transurethral resection of the bladder tumor (TURBT) is commonly advised in individuals with superficial bladder cancer, with or without intravesical therapy ( 3 ). The primarystay of therapy for muscle-invasive bladder cancer is radical cystectomy (RC) ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of aliphatic acid metabolism in bladder cancer with the goal of guiding therapeutic treatment

Song

He²,

Ning³

et al. 2022

Front. Oncol.

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Urothelial bladder cancer (BLCA) is a common internal malignancy with a poor prognosis. The re-programming of lipid metabolism is necessary for cancer cell growth, proliferation, angiogenesis and invasion. However, the role of aliphatic acid metabolism genes in bladder cancer patients has not been explored. The samples’ gene expression and clinicopathological data were obtained from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Univariate, multivariate, and LASSO Cox regression were used to develop a BLCA prognostic model. GSVA was used to assess function, whereas pRRophetic was used to assess chemotherapeutic drug sensitivity. The twelve-gene signature may define the tumor immune milieu, according to the risk score model. We compared the expression of aliphatic acid metabolism genes in malignant and non-cancerous tissues and chose 90 with a false discovery rate of 0.05 for The Cancer Genome Atlas cohort. The prognostic risk score model can effectively predict BLCA OS. A nomogram including age, clinical T stage, gender, grade, pathological stage, and clinical M stage was developed as an independent BLCA prognostic predictor. The halfmaximal inhibitory concentration (IC50) was used to assess chemotherapeutic medication response. Sorafenib and Pyrimethamine were used to treat patients with low risk scores more sensitively than patients with high risk scores. Immunotherapy candidates with CMS1 exhibited higher risk ratings. The aliphatic acid prognostic risk score model can assess metabolic trends. Clinical stage and molecular subtype may be used to categorize individuals using the risk score.With this new paradigm, future cancer treatment and immunotherapy may be tailored to the patient’s exact requirements.

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“…The advances in the understanding the pathogenesis of urothelial carcinoma have led to the development of new strategies, such as targeted therapies and ICI after failure of platinum-based therapy. Next-generation sequencing (NGS) has enabled us to acquire better knowledge of the genetic characteristics of BC with a better characterization of potential therapeutic targets [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Tyrosine Kinase Targets in Urothelial Carcinoma

Torres-Jiménez

Albarrán-Fernández

Pozas

et al. 2021

IJMS

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Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.

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Novel therapies in urothelial carcinoma: a biomarker-driven approach

Cited by 11 publications

References 75 publications

TP53 disruptive mutation predicts platinum‐based chemotherapy and PD‐1/PD‐L1 blockade response in urothelial carcinoma

TP53 disruptive mutation predicts platinum‐based chemotherapy and PD‐1/PD‐L1 blockade response in urothelial carcinoma

Evaluation of aliphatic acid metabolism in bladder cancer with the goal of guiding therapeutic treatment

Novel Tyrosine Kinase Targets in Urothelial Carcinoma

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