Antibody–drug conjugates in rare genitourinary tumors: review and perspectives

Current Opinion in Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

Rare cancers of the genitourinary (GU) tract are often clinically aggressive yet have few or no standard-of-care treatments. Multiple antibody-drug conjugates (ADCs) been approved in solid malignancies. This review explores use ADCs rare GU tumors context biological pathways and ongoing research tumors. Few clinical trials focus on recruiting participants with tract, including testing enfortumab vedotin as monotherapy combined pembrolizumab, sacituzumab govitecan atezolizumab. We highlight many novel for advanced/metastatic emphasize potential eligibility patients tumor-agnostic trials. being tested multiple tumors, Ongoing preclinical supports some several improves our understanding their pathophysiology.

Language: Английский

---

Leveraging real-world data to advance biomarker discovery and precision oncology

Cancer Cell, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

---

Strategies to overcome resistance to enfortumab vedotin and pembrolizumab for patients with urothelial carcinoma: harnessing present knowledge for future advances

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2025, Volume and Issue: 6

Published: April 7, 2025

The combination of enfortumab vedotin and pembrolizumab (EVP) has been recently approved for patients with locally advanced metastatic urothelial carcinoma. This showed a higher objective response rate superior progression-free survival overall over traditional platinum-based chemotherapy in the frontline setting pivotal EV-302 trial. Despite success, subset primary refractory disease, another will develop secondary resistance time. Resistance to may include downregulation nectin-4 expression minimize antibody binding, upregulation efflux pumps against toxin, or direct by tubulin toxin. includes several methods downregulate immune system. Additionally, type histology carcinoma likely plays an important role resisting EVP. review summarizes these possible mechanisms resistance, potential biomarkers predictive overcome

Language: Английский

---

Nectin-4 Expression Patterns and Therapeutics in Oncology

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217681 - 217681

Published: April 1, 2025

Language: Английский

---

High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy

Cell Reports, Journal Year: 2025, Volume and Issue: 44(4), P. 115545 - 115545

Published: April 1, 2025

Hyperglycemia is a recognized risk factor for bladder cancer (BC). Enfortumab vedotin (EV), the first NECTIN4-targeting antibody-drug conjugate, demonstrates promising clinical efficacy in patients with advanced BC. In this study, we show that EV treatment less effective BC diabetes than those normoglycemia. The subsequent vitro and vivo experiments indicate high glucose decreases sensitivity of cells to EV. Mechanistically, lactate overproduction associated promotes AARS1-mediated YTHDC1 lactylation enhances RNF183-mediated ubiquitination. Downregulated reduces JUND mRNA stability an m6A-dependent manner, subsequently decreasing NECTIN4 expression responsiveness. Our study identifies high-glucose-associated lactate-AARS1-YTHDC1-JUND-NECTIN4 axis affects Targeting activators or β-alanine may offer therapeutic strategies enhance

Language: Английский

---

Novel Molecular Biomarkers to Guide Treatment Decision-making in Metastatic Urothelial Cancer—A Patient Cohort Analysis

European Urology Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

The current options and recent developments in the field of systemic therapy for advanced urothelial cancer (UC) patients urge need selection criteria to identify most optimal therapeutic option individual patients. molecular makeup tumors, including subtype, tumor microenvironment composition, gene mutations, fusions, amplifications, has previously been correlated with a response immune checkpoint inhibitors, erdafitinib, or enfortumab vedotin (EV) monotherapy, may withhold potential candidate biomarkers. In this study, we aimed stratify metastatic UC (mUC) based on biomarkers that might be associated EV, fibroblast growth factor receptor inhibitor, anti-PD-(L)1, by using whole-genome DNA-sequencing paired RNA-sequencing data fresh-frozen biopsies 155 mUC We observed NECTIN4 amplification, FGFR2/3 RNA expression-based T-cell-to-stroma enrichment (TSE) score were mutually exclusive, therefore reflect biologically distinct tumors sensitivity treatments. This finding was validated two independent bladder cohorts: IMvigor210 study Cancer Genome Atlas. Stratification into subgroups these features is possible. Our challenge concept one-treatment-fits-all paradigm support rationale prospective clinical trials biomarker-guided treatment

Language: Английский

---

Membranous expression of target protein is required for ADC response in urothelial cancer

European Urology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

Language: Английский

---

Nectin-4 Positivity in Genitourinary Malignancies: A Systematic Review

JCO Precision Oncology, Journal Year: 2024, Volume and Issue: 8

Published: Dec. 1, 2024

PURPOSE Aberrant expression of nectin-4 (N4) has been observed in several malignancies emerging as new target for antibody-drug conjugates, especially urothelial carcinoma the bladder (UBC). Limited data on N4 positivity nonurothelial genitourinary (GU) cancers are available. This systematic-review aimed to investigate among GU malignancies. METHODS A systematic literature review was performed March 2023 using PubMed, MEDLINE, and Embase databases according Preferred Reporting Items Systematic Reviews Meta-Analyses statement. Protocol amended incorporate a updated search 2024. RESULTS Twenty-five studies evaluating tumors were included, 14 UBC, three upper tract (UTUC), six histologic subtypes (HS) divergent histology bladder, one papillary renal cell (pRCC), chromophobe RCC (chRCC), two penile cancer, prostate cancer (PCa). Among stratifying per stage higher metastatic (weighted mean [WM], 90.8; range, 59.6-100) non–muscle-invasive (WM, 87.4; 86.7-88.3) than muscle-invasive UC 83.1; 68.2-100). The UBC UTUC 62.9; 44.4-65.7). Immunohistochemistry reported be lower non-UC malignancies, including pRCC 44.1; 44.1-44.1), HS 63.5; 0-100), PCa (WM0; 0-0), chRCC 18.5; 18.5-18.5), 86.5; 61.4-98.3), compared with overall 87.1; 59.6-100). CONCLUSION Non-UC seem have rate UC. appears vary presence HS. predictive prognostic role must further characterized larger prospective studies.

Language: Английский

---

Oncologic Outcomes of Patients with Immune Checkpoint Inhibitor Resistant Urothelial Carcinoma Treated with Enfortumab Vedotin and the Impact of Neutrophil-to-Lymphocyte Ratio and Dysgeusia on Overall Survival: A Retrospective Multicenter Cohort Study in Japan

Cancers, Journal Year: 2024, Volume and Issue: 16(15), P. 2648 - 2648

Published: July 25, 2024

Randomized phase III trial results have demonstrated enfortumab vedotin (EV), an antibody–drug conjugate (ADC) consisting of anti-Nectin-4 human IgG1 monoclonal antibody and monomethyl auristatin E, is a useful treatment for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) that progressed after immune checkpoint inhibitor (ICI) therapies. This multicenter retrospective cohort study aimed to identify predictive factors the efficacy EV therapy prolonged overall survival (OS) in clinical practice. included la/mUC who received ICI treatment. Patients subsequently treatment, those non-EV chemotherapy, no were defined as EV, non-EV, best supportive care (BSC) groups, respectively. The median OS was 20, 15, 7 months BSC respectively (p < 0.001). had complete partial response significantly compared stable progressive disease. Univariate analysis showed age, neutrophil-to-lymphocyte ratio (NLR), dysgeusia, rash independent predictors improvement. NLR dysgeusia multivariate analysis. without these both factors. In real-world practice, effective

Language: Английский

---

Mechanistic Insights into the Successful Development of Combination Therapy of Enfortumab Vedotin and Pembrolizumab for the Treatment of Locally Advanced or Metastatic Urothelial Cancer

Cancers, Journal Year: 2024, Volume and Issue: 16(17), P. 3071 - 3071

Published: Sept. 4, 2024

Antibody–drug conjugates (ADCs) consist of an antibody backbone that recognizes and binds to a target antigen expressed on tumor cells small molecule chemotherapy payload is conjugated the via linker. ADCs are one most promising therapeutic modalities for treatment various cancers. However, many patients have developed resistance this form therapy. Extensive efforts been dedicated identifying effective combination with other types anticancer therapies potentially overcome resistance. A recent clinical study demonstrated ADC enfortumab vedotin (EV) immune checkpoint inhibitor (ICI) pembrolizumab can achieve remarkable efficacy as first-line therapy locally advanced or metastatic urothelial carcinoma (la/mUC)—leading first approval ICI cancer patients. In review, we highlight knowledge understanding gained from successful development EV la/mUC. Using example, will focus dissecting underlying mechanisms necessary type variety

Language: Английский

---