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High resolution proteomics approaches have been successfully utilized for the comprehensive characterization of the cell proteome. However, in the case of quantitative proteomics an open question still remains, which quantification strategy is best suited for identification of biologically relevant changes, especially in clinical specimens. In this study, a thorough comparison of a label-free approach (intensity-based) and 8-plex iTRAQ was conducted as applied to the analysis of tumor tissue samples from non-muscle invasive and muscle-invasive bladder cancer. For the latter, two acquisition strategies were tested including analysis of unfractionated and fractioned iTRAQ-labeled peptides. To reduce variability, aliquots of the same protein extract were used as starting material, whereas to obtain representative results per method further sample processing and MS analysis were conducted according to routinely applied protocols. Considering only multiple-peptide identifications, LC-MS/MS analysis resulted in the identification of 910, 1092 and 332 proteins by label-free, fractionated and unfractionated iTRAQ, respectively. The label-free strategy provided higher protein sequence coverage compared to both iTRAQ experiments. Even though pre-fraction of the iTRAQ labeled peptides allowed for a higher number of identifications, this was not accompanied by a respective increase in the number of differentially expressed changes detected. Validity of the proteomics output related to protein identification and differential expression was determined by comparison to existing data in the field (Protein Atlas and published data on the disease). All methods predicted changes which to a large extent agreed with published data, with label-free providing a higher number of significant changes than iTRAQ. Conclusively, both label-free and iTRAQ (when combined to peptide fractionation) provide high proteome coverage and apparently valid predictions in terms of differential expression, nevertheless label-free provides higher sequence coverage and ultimately detects a higher number of differentially expressed proteins. The risk for receiving false associations still exists, particularly when analyzing highly heterogeneous biological samples, raising the need for the analysis of higher sample numbers and/or application of adjustment for multiple testing.

Patients with metastatic castration-resistant prostate cancer (mCRPC) with extrapelvic soft-tissue metastases that has progressed on an androgen receptor pathway inhibitor (ARPI) have a poor prognosis with few treatment options. We aimed to assess efficacy and safety of cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, plus the PD-L1 inhibitor atezolizumab in these patients. CONTACT-02 is an open-label, randomised, phase 3 study that enrolled patients at 184 sites across 24 countries (in Europe, North America, Asia–Pacific, and Latin America). Men aged 18 years and older, with an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who had mCRPC and measurable extrapelvic soft-tissue metastases (lymph node or visceral) that had progressed on one previous ARPI were eligible. Patients were randomly assigned 1:1 to cabozantinib (40 mg orally once daily) plus atezolizumab (1200 mg intravenously once every 3 weeks) or ARPI switch (abiraterone 1000 mg orally once-daily plus prednisone 5 mg orally twice-daily, or enzalutamide 160 mg orally once-daily) using a web-based interactive response technology system and stratified by the presence of liver metastasis, previous docetaxel therapy, and disease status at first ARPI initiation. Dual primary endpoints were progression-free survival in the first 400 randomly assigned patients (progression-free survival intention-to treat [ITT] population) and overall survival in all randomly assigned patients (ITT population). Safety was assessed in all patients who received at least one dose of study treatment. Although the study is ongoing, with some patients remaining in follow-up, this analysis represents the protocol-specified final analysis. This trial is registered with ClinicalTrials.gov, NCT04446117. Between Aug 20, 2020 and June 7, 2023, 575 patients were randomly assigned to cabozantinib plus atezolizumab (n=289) or ARPI switch (n=286). Most patients were White (440 [77%]) or Asian (78 [14%]). After a median follow-up of 11·8 months (IQR 9·9–19·3), cabozantinib plus atezolizumab significantly improved progression-free survival versus ARPI switch (median 6·3 months [95% CI 6·2–8·8] vs 4·2 months [3·7–5·7]; hazard ratio [HR] 0·65 [95% CI 0·50–0·84], p=0·0007). After a median follow-up of 23·1 months (IQR 17·4–30·5), overall survival was not significantly different between the cabozantinib plus atezolizumab and ARPI switch groups (median 14·8 months [95% CI 13·4–16·7] vs 15·0 months [13·0–18·5]; HR 0·89 [95% CI 0·72–1·10], p=0·30). Any-cause grade 3–4 adverse events occurred in 158 (56%) of 284 patients given cabozantinib plus atezolizumab and 74 (26%) of 284 patients given ARPI switch; the most common in the cabozantinib plus atezolizumab group were hypertension (24 [8%] of 284 patients) and anaemia (23 [8%]) and the most common in the ARPI switch group was anaemia (18 [6%] of 284 patients). Serious adverse events deemed related to treatment occurred in 45 (16%) of 284 patients in the cabozantinib plus atezolizumab group and in 11 (4%) of 284 patients in the ARPI switch group; the most common with cabozantinib plus atezolizumab was diarrhoea (five [2%] of 284 patients) and the most common with ARPI switch was increase in alanine aminotransferase (two [1%] of 284 patients). Adverse events of any cause led to discontinuation of all components of study treatment in 49 (17%) of 284 patients in the cabozantinib plus atezolizumab group and in 42 (15%) of 284 patients in the ARPI switch group. No treatment-related deaths occurred. Cabozantinib plus atezolizumab, a novel drug combination that does not directly target androgen receptor signalling, could be a useful treatment option for patients with mCRPC and soft-tissue metastases who have progressed on an ARPI. Exelixis in partnership with Ipsen, Takeda, and Roche.

Although androgen deprivation therapy is typically given long-term for men with metastatic prostate cancer, second-generation hormone therapies are generally discontinued before the subsequent line of treatment. We aimed to evaluate the efficacy of continuing enzalutamide after progression in controlling metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel and prednisolone. PRESIDE was a two-period, multinational, double-blind, randomised, placebo-controlled, phase 3b study done at 123 sites in Europe (in Austria, Belgium, Czech Republic, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Russia, Spain, Sweden, Switzerland, Turkey, and the UK). Patients were eligible for period 1 (P1) of the study if they had histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features, serum testosterone concentrations of 1·73 nmol/L or less, and had progressed during androgen deprivation therapy with a luteinising hormone-releasing hormone agonist or antagonist or after bilateral orchiectomy. In P1, patients received open-label enzalutamide 160 mg per day orally. At week 13, patients were assessed for either radiographic or prostate-specific antigen (PSA) progression (25% or more increase and 2 ng/mL or more above nadir). Patients who showed any decline in PSA at week 13 and subsequently progressed (radiographic progression, PSA progression, or both) were screened and enrolled in period 2 (P2), during which eligible patients were treated with up to ten cycles of intravenous docetaxel 75 mg/m2 every 3 weeks and oral prednisolone 10 mg/day, and randomly assigned (1:1) to oral enzalutamide 160 mg/day or oral placebo. Patients were stratified by type of disease progression. The block size was four and the overall number of blocks was 400. Patients, investigators, and study organisers were masked to treatment assignment. The primary endpoint was progression-free survival analysed in all patients in P2. This trial is registered with ClinicalTrials.gov, NCT02288247, and is no longer recruiting. Between Dec 1, 2014, and Feb 15, 2016, 816 patients were screened for P1 of the study. 688 patients were enrolled in P1 and 687 received open-label enzalutamide. In P2, 271 patients were randomly assigned at 73 sites to receive enzalutamide (n=136) or placebo (n=135). The data cutoff for analysis was April 30, 2020. Median progression-free survival with enzalutamide was 9·5 months (95% CI 8·3–10·9) versus 8·3 months (6·3–8·7) with placebo (hazard ratio 0·72 [95% CI 0·53–0·96]; p=0·027). The most common grade 3 treatment-emergent adverse events were neutropenia (17 [13%] of 136 patients in the enzalutamide group vs 12 [9%] of 135 patients in the placebo group) and asthenia (ten [7%] vs six [4%]). The most common grade 4 treatment-emergent adverse event in P2 was neutropenia (23 [17%] of 136 patients in the enzalutamide group vs 28 [21%] of 135 patients in the placebo group). Serious treatment-emergent adverse events were reported in 67 (49%) of 136 patients in the enzalutamide group and 52 (39%) of 135 patients in the placebo group. Two (15%) of 13 deaths in the enzalutamide group (caused by septic shock and haematuria) and one (14%) of seven deaths in the placebo group (caused by actue kidney injury) were associated with docetaxel. PRESIDE met its primary endpoint and showed that continuing enzalutamide with docetaxel plus androgen deprivation therapy delayed time to progression compared with docetaxel plus androgen deprivation therapy alone, supporting the hypothesis that enzalutamide maintenance could control persistent androgen-dependent clones in men with mCRPC who progress after treatment with enzalutamide alone. Astellas Pharma and Pfizer.

The increasing volume and complexity of biomedical literature pose challenges for making scientific knowledge accessible to lay audiences. Lay summaries, now widely encouraged or required by journals, aim to bridge this gap by promoting health literacy, patient engagement, and public trust. However, many are written by scientists without formal training in plain-language communication, often resulting in limited clarity, readability, and consistency. Generative large language models such as ChatGPT-4 offer a scalable opportunity to support lay summary creation, though their effectiveness within specific clinical domains has not been systematically evaluated at scale. This study aimed to assess ChatGPT-4's performance in generating lay summaries for prostate cancer studies. A secondary objective was to evaluate how prompt design influences summary quality, aiming to provide practical guidance for the use of generative artificial intelligence (AI) in scientific publishing. A total of 204 consecutive articles on prostate cancer were extracted from a high-ranking oncology journal mandating lay summaries. Each abstract was processed with ChatGPT-4 using 2 prompts: a simple prompt based on the journal's guidelines and an extended prompt refined to improve readability. AI-generated and original summaries were evaluated using 3 criteria: readability (Flesch-Kincaid Reading Ease [FKRE]), factual accuracy (5-point Likert scale, blinded rating by 2 clinical experts), and compliance with word count instructions (120-150 words). Summaries were classified as high-quality as a composite outcome if they met all 3 benchmarks: FKRE >30, accuracy ≥4 from both raters, and word count within range. Statistical comparisons used Wilcoxon signed-rank and paired 2-tailed t tests (P<.05). ChatGPT-4-generated lay summaries showed an improvement in readability compared to human-written versions, with the extended prompt achieving higher scores than the simple prompt (median FKRE: extended prompt 47, IQR 42-56; simple prompt 36, IQR 29-43; original 20, IQR 9.5-29; P<.001). Factual accuracy was higher for the AI-generated lay summaries compared to originals (median factual accuracy score: extended prompt 5, IQR 5-5; simple prompt 5, IQR 5-5; original 5, IQR 4-5; P<.001) in this dataset. Compliance with word count instructions was greater for both AI-generated summaries in comparison to originals (wrong number of words; extended prompt 39 (19%), simple prompt 40 (20%), original 140 (69%); P<.001). Between simple and extended prompts, there were no significant differences in accuracy (P=.53) and word count compliance (P=.87). The proportion rated as high-quality was 79.4% for the extended prompt, 54.9% for the simple prompt, and 5.4% for original summaries (P<.001). With optimized prompting, ChatGPT-4 produced lay summaries that, on average, scored higher than author-written versions in readability, factual accuracy, and structural compliance within our dataset. These results support integrating generative AI into editorial workflows to improve science communication for nonexpert audiences. Limitations include focus on a single clinical domain and journal, and absence of layperson evaluation.

Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here. Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9–24·8] with docetaxel, prednisone, and custirsen vs 22·0 months [19·5–24·0] with docetaxel and prednisone; hazard ratio [HR] 0·93, 95% CI 0·79–1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 [13%] vs 28 [6%]; grade 4, 98 [20%] vs 77 [15%]), febrile neutropenia (grade 3, 52 [10%] vs 31 [6%]; grade 4, four [1%] vs two [<1%]), and fatigue (grade 3, 53 [11%] vs 41 [8%]; grade 4, three [1%] vs one [<1%]). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. OncoGenex Technologies.

Background: Molecular markers of clinical outcome may aid in designing targeted treatments for bladder cancer. However, only a few bladder cancer biomarkers have been examined as therapeutic targets. Methods: Data from The Cancer Genome Atlas (TCGA) and bladder specimens were evaluated to determine the biomarker potential of the hyaluronic acid (HA) family of molecules – HA synthases, HA receptors and hyaluronidase. The therapeutic efficacy of 4-methylumbelliferone (4MU), a HA synthesis inhibitor, was evaluated in vitro and in xenograft models. Results: In clinical specimens and TCGA data sets, HA synthases and hyaluronidase-1 levels significantly predicted metastasis and poor survival. 4-Methylumbelliferone inhibited proliferation and motility/invasion and induced apoptosis in bladder cancer cells. Oral administration of 4MU both prevented and inhibited tumour growth, without dose-related toxicity. Effects of 4MU were mediated through the inhibition of CD44/RHAMM and phosphatidylinositol 3-kinase/AKT axis, and of epithelial–mesenchymal transition determinants. These were attenuated by HA, suggesting that 4MU targets oncogenic HA signalling. In tumour specimens and the TCGA data set, HA family expression correlated positively with β -catenin, Twist and Snail expression, but negatively with E-cadherin expression. Conclusions: This study demonstrates that the HA family can be exploited for developing a biomarker-driven, targeted treatment for bladder cancer, and 4MU, a non-toxic oral HA synthesis inhibitor, is one such candidate.

Urothelial bladder cancer (UC) has a wide tumor biological spectrum with challenging prognostic stratification and relevant therapy-associated morbidity. Most molecular classifications relate only indirectly to the therapeutically relevant protein level. We improve the pre-analytics of clinical samples for proteome analyses and characterize a cohort of 434 samples with 242 tumors and 192 paired normal mucosae covering the full range of UC. We evaluate sample-wise tumor specificity and rank biomarkers by target relevance. We identify robust proteomic subtypes with prognostic information independent from histopathological groups. In silico drug prediction suggests efficacy of several compounds hitherto not in clinical use. Both in silico and in vitro data indicate predictive value of the proteomic clusters for these drugs. We underline that proteomics is relevant for personalized oncology and provide abundance and tumor specificity data for a large part of the UC proteome ( www.cancerproteins.org ). Urothelial cancer is a challenging disease and an emerging field for targeted therapies. Here, the authors optimize clinical proteomics to provide proteome-level data on tumor specificity and identify robust prognostic subtypes with predictive information for repurposed drug candidates.

Urinary profiling datasets, previously acquired by capillary electrophoresis coupled to mass-spectrometry were investigated to identify a general urinary marker pattern for detection of solid tumors by targeting common systemic events associated with tumor-related inflammation. A total of 2,055 urinary profiles were analyzed, derived from a) a cancer group of patients (n = 969) with bladder, prostate, and pancreatic cancers, renal cell carcinoma, and cholangiocarcinoma and b) a control group of patients with benign diseases (n = 556), inflammatory diseases (n = 199) and healthy individuals (n = 331). Statistical analysis was conducted in a discovery set of 676 cancer cases and 744 controls. 193 peptides differing at statistically significant levels between cases and controls were selected and combined to a multi-dimensional marker pattern using support vector machine algorithms. Independent validation in a set of 635 patients (293 cancer cases and 342 controls) showed an AUC of 0.82. Inclusion of age as independent variable, significantly increased the AUC value to 0.85. Among the identified peptides were mucins, fibrinogen and collagen fragments. Further studies are planned to assess the pattern value to monitor patients for tumor recurrence. In this proof-of-concept study, a general tumor marker pattern was developed to detect cancer based on shared biomarkers, likely indicative of cancer-related features.

Background Extracellular vesicles (EVs), including microvesicles, hold promise for the management of bladder urothelial carcinoma (BLCA), particularly because of their utility in identifying therapeutic targets and their diagnostic potential using easily accessible urine samples. Among the transmembrane glycoproteins highly enriched in cancer-derived EVs, tissue factor (TF) and CD147 have been implicated in promoting tumor progression. In this in vitro study, we explored a novel approach to impede cancer cell migration and metastasis by simultaneously targeting these molecules on urothelial cancer-derived EVs. Methods Cell culture supernatants from invasive and non-invasive bladder cancer cell lines and urine samples from patients with BLCA were collected. Large, microvesicle-like EVs were isolated using sequential centrifugation and characterized by electron microscopy, nanoparticle tracking analysis, and flow cytometry. The impact of urinary or cell supernatant-derived EVs on cellular phenotypes was evaluated using cell-based assays following combined treatment with a specific CD147 inhibitor alone or in combination with a tissue factor pathway inhibitor (TFPI), an endogenous anticoagulant protein that can be released by low-molecular-weight heparins. Results We observed that EVs obtained from the urine samples of patients with muscle-invasive BLCA and from the aggressive bladder cancer cell line J82 exhibited higher TF activity and CD147 expression levels than did their non-invasive counterparts. The shedding of GFP-tagged CD147 into isolated vesicles demonstrated that the vesicles originated from plasma cell membranes. EVs originating from invasive cancer cells were found to trigger migration, secretion of matrix metalloproteinases (MMPs), and invasion. The same induction of MMP activity was replicated using EVs obtained from urine samples of patients with invasive BLCA. EVs derived from cancer cell clones overexpressing TF and CD147 were produced in higher quantities and exhibited a higher invasive potential than those from control cancer cells. TFPI interfered with the effect when used in conjunction with the CD147 inhibitor, further suppressing homotypic EV-induced migration, MMP production, and invasion. Conclusions Our findings suggest that combining a CD147 inhibitor with low molecular weight heparins to induce TFPI release may be a promising therapeutic approach for urothelial cancer management. This combination can potentially suppress the tumor-promoting actions of cancer-derived microvesicle-like EVs, including collective matrix invasion. Graphical Abstract Highlights • Invasive bladder cancer cells shed extracellular vesicles (EVs) that contain tissue factor (TF) and CD147. • Tumor-derived EVs can promote cancer cell migration and invasion. • A combination of a CD147 inhibitor and tissue factor pathway inhibitor (TFPI) can suppress the cancer-promoting actions of EVs. Plain summary Small particles or vesicles released by cancer cells into their surroundings have the potential to stimulate the spread and growth of cancer cells. In this study, we focused on two specific molecules presented by these cancer cell-derived vesicles that could play a role in promoting the dissemination of cancer cells: a protein related to blood clotting and a protein on the cell surface. We found that large vesicles from bladder cancer cells that have the ability to spread had higher levels of these proteins than vesicles from nonspreading cancer cells. We also found that the former could make cancer cells move about more, produce more of a substance that helps cancer cells spread, and invade other tissues. To counteract the cancer-promoting actions of these vesicles, we examined the impact of combining a naturally occurring anticlotting protein that can be released by medications derived from heparin with an inhibitor targeting the cancer cell surface protein. We found that this combination stopped the vesicles from helping cancer cells move about more, produce more of the spreading substance, and invade other tissues. This approach of simultaneously targeting the two protein molecules present on cancer cell-derived vesicles might be a new way to treat bladder cancer.

VEGF-targeted therapy increases both the progression-free (PFS) and overall survival (OS) of patients with metastasized renal cell cancer (mRCC). Identification of molecular phenotypes of RCC could improve risk-stratification and the prediction of the clinical disease course. We investigated whether gene-specific DNA hypermethylation can predict PFS and OS among patients undergoing anti-VEGF-based therapy. Primary tumor tissues from 18 patients receiving targeted therapy were examined retrospectively using quantitative methylation-specific PCR analysis of CST6, LAD1, hsa-miR-124-3, and hsa-miR-9-1 CpG islands. PFS and OS were analyzed for first-line and sequential antiangiogenic therapies using the log rank statistics. Sensitivity and specificity were determined for predicting first-line therapy failure. Hypermethylation of CST6 and LAD1 was associated with both a shortened PFS (log rank p = 0.009 and p = 0.004) and OS (p = 0.011 and p = 0.043). The median PFS observed for the high and low methylation groups of CST6 and LAD1 was 2.0 vs.11.4 months. LAD1 methylation had a specificity of 1.0 (95% CI 0.65-1.0) and a sensitivity of 0.73 (95% CI 0.43-0.90) for the prediction of first-line therapy. CST6 and LAD1 methylation are candidate epigenetic biomarkers showing unprecedented association with PFS and OS as well as specificity for the prediction of the response to therapy. DNA methylation markers should be considered for the prospective evaluation of larger patient cohorts in future studies.