Enfortumab vedotin and pembrolizumab: redefining the standard of care for previously untreated advanced urothelial cancerSternschuss, Rosenberg
Future Oncol (2025)
Abstract: Combination treatment with Enfortumab vedotin (EV), an antibody drug conjugate targeting Nectin-4 with a monomethyl auristatin E (MMAE) payload, and pembrolizumab, a programmed death 1 (PD-1) inhibitor, has become the new standard of care for previously untreated locally advanced or metastatic urothelial carcinoma. In the recently published phase III study, EV-302, EV and pembrolizumab demonstrated improved outcomes compared to platinum-based chemotherapy, including objective response rate, progression free survival, and an unprecedented median overall survival of 33.8 months (versus 15.9 months; hazard ratio for death 0.51; 95% confidence interval 0.43-0.61; p < 0.00001). We reviewed the mechanism of action, clinical efficacy, exploratory biomarkers, and safety profile of EV and pembrolizumab as monotherapies and combination in urothelial cancer.
Theranostic implications of Nectin-4 oncoprotein in gynecologic cancers: A reviewHooks, Nagpal, Childers
et alPathol Res Pract (2025) 269, 155913
Abstract: Gynecologic cancers, in order of prevalence, include uterine, ovarian, cervical, vaginal, and vulvar cancers. In 2024, there will be more than 116,000 new cases of gynecologic cancers and 33,800 disease-related deaths. Therefore, a concerted effort has been made to better understand the underlying pathophysiological processes and identify novel theranostic approaches.Comprehensively examine the current peer-reviewed literature surrounding Nectin-4 and its implication in the identification and treatment of gynecologic cancers.PubMed and Google search with relevant keywords for articles published in the last 15 years.Nectin-4 as a cell adhesion molecule (CAM) promotes cell growth through intra-tumoral angiogenesis, strengthens cell-cell bonds, and creates a tight spheroid structure, which is more chemotherapy resistant. In high-grade serous ovarian cancer (HGSOC), Nectin-4 is strongly associated with the presence of peritoneal metastases and worse prognoses. When compared to CA-125, a common tumor marker for ovarian cancer, Nectin-4 showed higher specificity and sensitivity for predictive value of tumorigenesis. Regarding cervical cancer, inhibition of Nectin-4 by nanoformulated Quinacrine inhibits both cancer stem cell proliferation and DNA damage. Nectin-4 as a tumor marker can discriminate endometrial cancer from healthy adjacent tissue with a specificity of 95.4 % and sensitivity of 82.81 %. Lastly, there is scarce evidence of Nectin-4 and fallopian tube, vaginal, or vulvar cancer but given ovarian cancer cells may originate from the fallopian tube, there is plausibility of using Nectin-4 to detect fallopian and/or ovarian cancer earlier.Overall, Nectin-4 as a promoter of cancer cell growth and metastasis supports the emphasis in current peer-reviewed literature as an effective theranostic biomarker.Copyright © 2025 Elsevier GmbH. All rights reserved.
A Peptide Derived from Nectin-4 Increases Cisplatin Cytotoxicity in Cell Lines and Cells from Ovarian Cancer Patients' AscitesBoylan, Walz, Schefter
et alCancers (Basel) (2025) 17 (5)
Abstract: New approaches to the treatment of women with ovarian cancer are desperately needed, since most women develop resistance to chemotherapy and the 5-year survival rate remains low. The hypothesis guiding this study was that the inhibition of cell adhesion could be used as a novel strategy to increase the chemosensitivity of ovarian cancer cells.The Nectin-4 peptide N4-P10 was used to inhibit the formation of cell-cell aggregates (spheroids) using cell lines and cells isolated from ovarian cancer patients' ascites. Cell lines were pre-treated with peptide N4-P10 or control scrambled peptides and monitored for spheroid formation with live-cell imaging by digital time-lapse photography. Cells were then tested for the cytotoxicity of the chemotherapeutic agent, cisplatin.Peptide N4-P10 blocked aggregation in cell lines with different levels of Nectin-4 expression and different spheroid morphologies. The cytotoxicity of cisplatin increased in cells pre-treated with peptide N4-P10. Similarly, when single cells were isolated from the ascites of ovarian cancer patients, peptide N4-P10 blocked cell aggregation and increased the cytotoxicity of cisplatin.These results suggest that targeting the cell-cell adhesive property of cancer cells could serve as a new approach to augment the cytotoxic effect of chemotherapy and potentially reduce disease recurrence in ovarian cancer patients.
Uncovering potential targets for antibody-drug conjugates in the treatment of gynecologic malignanciesJiang, Xu, He
et alFront Pharmacol (2025) 16, 1525733
Abstract: Antibody-drug conjugates (ADCs) play an important role in the targeted therapy of gynecological malignancies. The purpose of this study was to investigate the expression of targets in gynecologic malignancies in order to predict the selection of targets for the development of antibody-drug conjugates.In this article, we identified existing ADCs and their targets through clinical trial databases and public genomic datasets, performed differential analysis of tumor antigen targets (TATs) expression between tumor and normal tissues, and evaluated the necessity of the targets for tumor cell lines.In gynecologic malignancies, we have identified several highly expressed TATs, some of which have been targeted by FDA-approved ADCs, such as TROP2 and Nectin-4, although these drugs have not been approved for the treatment of gynecologic cancers. At the same time, we also observed that some targets of ADCs that have not yet been approved by the FDA also show high expression levels in gynecologic malignancies tissues, such as MSLN, ERBB3, NaPi2b, etc. Furthermore, we identified TATs with high expression levels in various pathological subtypes of ovarian, endometrial, and cervical cancer. Notably, some TATs are crucial to the survival of tumor cells, such as CD71, TOP1, and TDGF1, which are essential for the survival of ovarian, endometrial, cervical, and other tumor cells.We have innovatively predicted the potential targets of ADCs in treating gynecological malignancies and provided a new perspective on applying some FDA-approved ADCs in indications for gynecological cancers.Copyright © 2025 Jiang, Xu, He, Sui, Li, Xia and Yao.
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