Search Results (108)

Objectives: The aim of this study was to assess the association of diabetes mellitus and its medications with overall response (ORR) and mortality or cancer-specific survival (CSS) in patients with metastatic urothelial cancer receiving enfortumab vedotin monotherapy. Methods: This multicentre retrospective cohort study was designed according to the guidelines for the synthesis of qualitative research (ENTREQ). Eligible patients were adults (≥18) years treated with enfortumab vedotin monotherapy for metastatic urothelial cancer between June 2024 and January 2025. A total of 125 patients were reported across 11 centres. Results: The cohort included 93 males (74.4%) and 32 females (25.6%), with a mean age of 68.3 years (SD 9.3). The primary tumour site was the bladder in 109 (87.2%) cases and the upper tract (UTUC) in 16 (12.8%) cases. Interestingly, medication with metformin was significantly associated with cancer-specific mortality (37.9% versus 77.8%; p = 0.019), while patients with insulin-dependent diabetes mellitus had a significantly better CSS (Log Rank = 0.004). Upon comparing only patients who already had diabetes mellitus and then received anti-diabetic medication, there was a significant association between patients with diabetes mellitus receiving metformin and a worse 3-month ORR (80.0% versus 55.6%; p = 0.039). Regarding the subpopulation of UTUC, cancer-specific mortality was significantly associated with metformin medication (p = 0.033). Conclusions: Despite recent reports that metformin has protective effects in urothelial cancer, our findings suggest that metformin use may be linked to worse responses and survival outcomes in patients treated with enfortumab vedotin monotherapy. Further research, particularly translational research into the underlying diabetic and pharmacologic pathways, is warranted. Full article

Background: Lactate dehydrogenase (LDH) activity, producing high levels of lactate from pyruvate in cancer cells, is often associated with poor patient prognosis. We previously showed enhanced LDH/lactate levels in estrogen receptor (ER) compared to ER + breast cancer cells; lactate or pyruvate supplementation to ER + cells significantly enhanced their motile ability, while LDHB gene knockout (KO) or treatment with LDH inhibitors reduced the motility of the highly aggressive ER breast cancer cells. Aims: To investigate the molecular mechanisms by which lactate, LDHB KO, or treatment with LDH inhibitors can modulate the motile capabilities of breast cancer cell lines. Methods: KO experiments were performed using siRNA, and global expression was determined by proteomic profiling with Proteome Profiler Human XL Oncology arrays, Western blot, and immunofluorescence. Results: Lactate supplementation to ER + breast cancer cells enhanced expression of vimentin, N-cadherin, and snail, while reducing the expression of JAM-A, E-cadherin, and nectin-4. This expression profile was reversed with LDHB KO in ER cells. LDHB KO, or treatment with LDH inhibitors in ER cells, also reduced the expression of IL-6, IL-8, and MMP-2. The expressions of other markers such as PECAM-1, CCL20, and ENPP-2 were differentially modulated with LDH B KO in de novo ER cells (MDA-MB-231) vs. those that had ER knockout (pII). Conclusions: Our data show a novel role for lactate in modulating the EMT status in breast cancer cells and highlight the important role of lactate in breast cancer motility in part through modulating EMT status and the expression profile of cytokines, adhesion molecules, MMP-2, and nectin-4. Full article

Antibody–drug conjugates (ADCs) represent a novel approach to cancer treatment. Enfortumab vedotin (PADCEV), as a prominent example, has demonstrated remarkable clinical efficacy. However, its ocular toxicity has raised concerns. This study aimed to explore the molecular mechanisms underlying PADCEV—induced ocular toxicity. SD rats, whose ocular structures are similar to those of humans, were selected to establish an ocular toxicity model to mimic the human response. In vitro experiments were conducted using human primary corneal epithelial cells, HCE-T. The results confirmed that nectin-4 plays a crucial role in the cellular uptake of PADCEV, and non-specific pinocytosis is also involved. Additionally, a variant was obtained by introducing point mutations in the Fc region of PADCEV, which was found to reduce corneal epithelial toxicity. The findings of this study not only deepen our understanding of ADC-induced ocular toxicity but also provide new insights into optimizing ADC design and enhancing treatment safety. Full article

Background/Objectives: Urothelial carcinoma (UC) treatment has been transformed by immunotherapy and antibody-drug conjugates (ADCs). This review evaluates the current evidence for these approaches and identifies future directions. Methods: We conducted a structured review of clinical trials, meta-analyses, and guidelines published until early 2025. Results: Immune checkpoint inhibitors have established benefits across multiple settings: post-platinum therapy (pembrolizumab, nivolumab), maintenance therapy (avelumab), adjuvant settings for high-risk muscle-invasive disease (nivolumab), and BCG-unresponsive non-muscle-invasive disease (pembrolizumab). Enfortumab vedotin (targeting Nectin-4) has proven effective in post-platinum/post-immunotherapy. Most significantly, enfortumab vedotin plus pembrolizumab has redefined first-line treatment with unprecedented survival benefits (median OS 31.5 months vs. 16.1 months with chemotherapy; HR 0.47), and nivolumab plus gemcitabine-cisplatin improved outcomes in cisplatin-eligible patients. Key challenges include managing unique toxicity profiles, optimizing treatment sequencing, and developing reliable biomarkers. Conclusions: Combination approaches offer the most promising path forward, with future research needed on resistance mechanisms, biomarker development, and expanding these therapies to earlier disease stages. Full article

Nectin-2 and Nectin-4 are cell adhesion molecules associated with the progression of various cancers. The main goal of this pilot study was to evaluate the expression patterns of Nectin-2 and Nectin-4 in laryngeal squamous cell carcinoma (LSCC). A retrospective study was conducted on tissue microarray (TMA) samples derived from 31 patients who underwent total laryngectomy. The findings revealed heterogenous expression of both Nectin-2 and Nectin-4 in tumor cells and surrounding stroma, with Nectin-4 expression being significantly higher than Nectin-2 expression. Specifically, 74% of cases showed weak cytoplasmic staining for Nectin-2, while 41.93% exhibited strong cytoplasmic staining for Nectin-4. Both Nectin-2 and Nectin-4 expressions were more pronounced at the invasive tumor margins. Although no significant differences in Nectin-4 expression were observed across tumor grades (W = 83.500; z = −0.463; p = 0.658), differences in expression patterns were noted. Well-differentiated tumors (Grade 1), 80.65% of cases, showed predominantly membranous Nectin-4 staining, including in squamous epithelial cells of the mucosal surface. Conversely, in less-differentiated tumors (Grade 2 and 3), a shift toward cytoplasmic staining was evident. Specifically, 74.19% of Grade 2 tumors and 100% of Grade 3 tumors showed a predominant cytoplasmic localization of Nectin-4. This transition from membranous to cytoplasmic localization was also evident in the progression from normal superficial epithelium to malignant tissue. These observations suggest that alterations in the expression and subcellular localization of Nectin-4 may be associated with carcinogenesis and could serve as potential markers for the assessment of precancerous lesions and the aggressiveness of laryngeal tumors. Full article

Nectins constitute a family of Ca(2+)-independent immunoglobulin-like adhesion molecules. They are involved in cell proliferation, morphogenesis, growth, development, and immune modulation. Due to their broad involvement in physiological processes, extensive research is being conducted on the expression of individual nectins in a variety of cancers and their potential in diagnosis, prognosis, and treatment. The overexpression of nectin-1 may be a poor prognostic factor in gastrointestinal cancers (intestine and pancreas). Similarly, the overexpression of nectin-2 is a worse prognostic factor (greater tumor advancement and shorter patient survival) in cancers such as gallbladder, esophagus, and breast cancer. Changes in nectin-3 expression also affect the advancement of, e.g., colorectal cancer. Additionally, a significant factor here seems to be the change in the localization of nectin-3 expression within cellular structures. The most extensively studied nectin-4 also shows prognostic potential in many cancers. Most often, its high expression correlates with poor prognosis (e.g., gastric cancer), but it may also be a positive prognostic factor, e.g., in salivary gland cancer. Therapy based on nectin-4 is already known and used in the case of urothelial cancers. The expression of nectin-like protein 5 (necl-5) also shows prognostic and therapeutic potential in pancreatic and lung cancers, as well as in multiple myeloma. Full article

Background/Objectives: 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. Methods: 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. Results: 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. Conclusions: 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. Full article

Background/Objectives: Observational studies suggest a link between vascular calcification and dementia or cognitive decline, but the evidence is conflicting, and the underlying mechanisms are unclear. Here, we investigate the shared genetic and causal relationships of vascular calcification—coronary artery calcification (CAC) and abdominal aortic calcification (AAC)—with Alzheimer’s disease (AD), and five cognitive traits. Methods: We analyse large-scale genome-wide association studies (GWAS) summary statistics, using well-regarded methods, including linkage disequilibrium score regression (LDSC), Mendelian randomisation (MR), pairwise GWAS (GWAS-PW), and gene-based association analysis. Results: Our findings reveal a nominally significant positive genome-wide genetic correlation between CAC and AD, which becomes non-significant after excluding the APOE region. CAC and AAC demonstrate significant negative correlations with cognitive performance and educational attainment. MR found no causal association between CAC or AAC and AD or cognitive traits, except for a bidirectional borderline-significant association between AAC and fluid intelligence scores. Pairwise-GWAS analysis identifies no shared causal SNPs (posterior probability of association [PPA]3 < 0.5). However, we find pleiotropic loci (PPA4 > 0.9), particularly on chromosome 19, with gene association analyses revealing significant genes in shared regions, including APOE, TOMM40, NECTIN2, and APOC1. Moreover, we identify suggestively significant loci (PPA4 > 0.5) on chromosomes 1, 6, 7, 9 and 19, implicating pleiotropic genes, including NAV1, IPO9, PHACTR1, UFL1, FHL5, and FOCAD. Conclusions: Current findings reveal limited genetic correlation and no significant causal associations of CAC and AAC with AD or cognitive traits. However, significant pleiotropic loci, particularly at the APOE region, highlight the complex interplay between vascular calcification and neurodegenerative processes. Given APOE’s roles in lipid metabolism, neuroinflammation, and vascular integrity, its involvement may link vascular and neurodegenerative disorders, pointing to potential targets for further investigation. Full article

Background: Antibody–drug conjugates (ADCs) represent a novel therapeutic class that combines an antibody against a tumor-associated antigen (TAA), a payload, and a linker that binds these two components. Serious adverse events (SAEs), particularly those of grade 3 (G3) or higher, frequently contribute to the abandonment of ADCs during clinical development. Methods: In this study, we analyzed the toxicity profiles of all approved ADCs, aiming to uncover correlations between their safety profiles and the specific characteristics of their components. Results: In our analysis, dose reductions, dose delays, treatment discontinuations, and ≥G3 toxicities were not significantly different across payload types. Similarly, no association was found between the payload mechanism of action and ≥G3 toxicities, including anemia, neutropenia, febrile neutropenia, thrombocytopenia, and diarrhea. By exploring the specific toxicities of ADCs observed by organ, we identified that most were related to the payload mechanism of action, like the ≥G3 diarrhea observed in 10% of patients treated with sacituzumab govitecan (the payload SN-38 is the active metabolite of irinotecan), and very few were related to the presence of the TAA in normal tissue (presence of Nectin-4 in skin and ≥G3 rash toxicity in 14% of patients treated with enfortumab vedotin). In line with this, no major differences in ≥G3 toxicities were identified in studies with different levels of the TAA (trastuzumab deruxtecan in Destiny Breast Studies with different HER2 expression levels). Conclusions: Our analysis reveals that most ADC toxicities are driven by the payload’s effects on non-transformed tissues; however, a detailed analysis of each ADC component should be taken into consideration. Full article

Herpes simplex viruses (HSV-1 and HSV-2), which can be transmitted both orally and sexually, cause lifelong morbidity and in some cases, meningitis and encephalitis. While both the passive transfer of neutralizing antibodies and placental transfer of anti-HSV monoclonal antibodies (Mabs) have shown therapeutic promise in animal models, clinical trials have yet to identify approved immunotherapeutics for herpes infection. Here, we present strategies for the generation of recombinant bispecific antibodies (BsAbs) that target different domains of glycoprotein D (gD), crucial for HSV entry, that have the potential to outperform the effect of individual Mabs to curb herpes infection. Specifically, we selected three pairs of Mabs from our extensive panel for BsAb design and production based on their binding site and ability to block virus entry. Actual binding of BsAbs to gD and epitope availability on gD after BsAb binding were characterized using surface plasmon resonance (SPR) and inhibition by IgG Fab fragments generated from selected Mabs. While one BsAb exhibited an additive effect similar to that observed using a combination of the Mabs utilized for its generation, two showed antagonistic effects, suggesting that the simultaneous engagement of two epitopes or selective binding to one affected their activity against HSV. One BsAb (DL11/1D3) targeting the binding site for both nectin-1 and HVEM receptors demonstrated synergistic inhibitory activity against HSV, outperforming the effect of the individual antibodies. Recombinant DL11/1D3 antibody variants, in which the size of one or both paratopes was decreased to single chains (scFv-Fc), highlighted differences in potency depending on antibody size and format. We propose that BsAbs to individual glycoproteins offer a potential avenue for herpes therapeutics, but their design, mechanism of action, antibody format, and epitope engagement require careful consideration of structure for optimal efficacy. Full article

Background: The role of molecular imaging in urothelial cancer is less defined than other cancers, and its utility remains controversial due to limitations such as high urinary tracer excretion, complicating primary tumour assessment in the bladder and upper urinary tract. This review explores the current landscape of PET imaging in the clinical management of urothelial cancer, with a special emphasis on potential future advancements including emerging novel non-¹⁸F FDG PET agents, PET radiopharmaceuticals, and PET-MRI applications. Methods: We conducted a comprehensive literature search in the PubMed database, using keywords such as “PET”, “PET-CT”, “PET-MRI”, “FDG PET”, “Urothelial Cancer”, and “Theranostics”. Studies were screened for relevance, focusing on imaging modalities and advances in PET tracers for urothelial carcinoma. Non-English language, off-topic papers, and case reports were excluded, resulting in 80 articles being selected for discussion. Results: ¹⁸F FDG PET-CT has demonstrated superior sensitivity over conventional imaging, such as contrast-enhanced CT and MRI, for detecting lymph node metastasis and distant disease. Despite these advantages, FDG PET-CT is limited for T-staging of primary urothelial tumours due to high urinary excretion of the tracer. Emerging evidence supports the role of PETC-CT in assessing response to neoadjuvant chemotherapy and in identifying recurrence, with a high diagnostic accuracy reported in several studies. Novel PET tracers, such as ⁶⁸Ga-labelled FAPI, have shown promising results in targeting cancer-associated fibroblasts, providing higher tumour-to-background ratios and detecting lesions missed by traditional imaging. Antibody-based PET tracers, like those targeting Nectin-4, CAIX, and uPAR, are under investigation for their diagnostic and theranostic potential, and initial studies indicate that these agents may offer advantages over conventional imaging and FDG PET. Conclusions: Molecular imaging is a rapidly evolving field in urothelial cancer, offering improved diagnostic and prognostic capabilities. While ¹⁸F FDG PET-CT has shown utility in staging, further prospective research is needed to establish and refine standardised protocols and validate new tracers. Advances in theranostics and precision imaging may revolutionise urothelial cancer management, enhancing the ability to tailor treatments and improve patient outcomes. Full article

The present review provides a detailed and comprehensive discussion on antibody–drug conjugates (ADCs) as an evolving new modality in the current therapeutic landscape of malignant diseases. The principle concepts of targeted delivery of highly toxic agents forsaken as stand-alone drugs are examined in detail, along with the biochemical and technological tools for their successful implementation. An extensive analysis of ADCs’ major components is conducted in parallel with their function and impact on the stability, efficacy, safety, and resistance profiles of the immunoconjugates. The scope of the article covers the major classes of currently validated natural compounds used as payloads, with an emphasis on their structural and mechanistic features, natural origin, and distribution. Future perspectives in ADCs’ design are thoroughly explored, addressing their inherent or emerging challenges and limitations. The survey also provides a comprehensive overview of the molecular rationale for active tumor targeting of ADC-based platforms, exploring the cellular biology and clinical relevance of validated tumor markers used as a “homing” mechanism in both hematological and solid tumor malignancies. Full article

Herpes simplex virus (HSV) is sexually transmitted via the anogenital mucosa where it initially infects epidermal keratinocytes and mononuclear phagocytes (MNPs). It then spreads to the dorsal root ganglion via sensory nerve endings, to remain latent for life with periodic reactivation. Currently, there is no cure or vaccine. Initial or recurrent HSV infection can produce serious complications and mediate acquisition of HIV. This review outlines the initial events after the HSV infection of human anogenital mucosa to determine the optimal window to target the virus before it becomes latent. After infection, HSV spreads rapidly within the mid-layers of epidermal keratinocytes in the explanted human inner foreskin. Infected cells produce chemokines, which modulate nectin-1 distribution on the surface of adjacent keratinocytes, facilitating viral spread. Epidermal Langerhans cells and dendritic cells become infected with HSV followed by a “viral relay” to dermal MNPs, which then present viral antigen to T cells in the dermis or lymph nodes. These data indicate the need for interruption of spread within 24 h by diffusible vaccine-induced mediators such as antiviral cytokines from resident immune cells or antibodies. Intradermal/mucosal vaccines would need to target the relevant dermal MNPs to induce HSV-specific CD4⁺ and CD8⁺ T cells. Full article

Background/Objectives: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) that combines monomethyl auristatin E (MMAE), a potent cytotoxic agent, with a monoclonal antibody targeting Nectin-4. It has emerged as a promising therapy for metastatic urothelial carcinoma (mUC), either as monotherapy or in combination with pembrolizumab, improving significantly the overall survival of these patients. EV is associated with common adverse events, including skin reactions, glucose imbalance, and peripheral neuropathy, which are usually mild in severity and easily manageable. Methods: Following an initial case of pleuro-pneumopathy occurring in a patient treated with EV, we conducted a retrospective analysis of EV effects on pulmonary imaging. Results: In a cohort of 20 all-comers mUC patients, we identified three cases of potentially EV-related lung toxicity, resulting in a pleuro-pneumopathy rate of 15%. Two of these cases appeared highly symptomatic and required high steroid doses, with a rapid resolution of symptoms and normalization of radiological findings. In one patient, rechallenge of EV was associated with reoccurrence of pneumopathy. We described the clinical and radiological features of these cases, as well as their evolution after EV discontinuation and rechallenge. Conclusions: This case series underscores the importance of close pulmonary monitoring during EV treatment. Full article