Yair Lotan | PubMed Health

PubMed2026

Clinical Validation of a Multiplex Urine Biomarker Assay for Surveillance of Recurrent Bladder Cancer.

PURPOSE: More than 50% of patients with non-muscle-invasive bladder cancer experience recurrence, requiring lifelong surveillance with repeated cystoscopy. Given the invasive nature and cost of cystoscopy, accurate noninvasive tools are needed to support risk-adapted monitoring. We evaluated the ability of Oncuria-Monitor, a multiplex urine biomarker assay, to detect recurrent bladder cancer during surveillance. PATIENTS AND METHODS: Between February 2017 and August 2020, six medical centers in the United States and Japan prospectively enrolled 300 patients with a history of bladder cancer, generating 1,248 serial urine samples. Participants were divided into training and validation cohorts. At each surveillance visit over 2 years, urine samples were analyzed in a blinded manner using Oncuria-Monitor and BladderChek, alongside urine cytology. Test performance was compared with cystoscopy and histopathology-confirmed recurrence. RESULTS: Recurrent bladder cancer was identified in 31% (93/300) of participants, with 143 total recurrences during follow-up, including 90 tumors in the validation cohort. In the validation cohort, Oncuria-Monitor achieved a sensitivity of 85.6% [95% confidence interval (CI), 78.1%-92.2%] and a negative predictive value (NPV) of 93% (95% CI, 89.2%-96.4%). In comparison, BladderChek demonstrated a sensitivity of 20.0% and an NPV of 88%, whereas urine cytology showed a sensitivity of 36.9% and an NPV of 91.6%. The number needed to evaluate to detect one recurrence was 3 for both cystoscopy and Oncuria-Monitor, compared with 15 for BladderChek and 8 for cytology. CONCLUSIONS: In this large prospective longitudinal study, Oncuria-Monitor demonstrated clinically actionable performance, enabling a rule-out strategy that could safely reduce cystoscopy in approximately 25% of surveillance visits. These findings support a paradigm shift toward biomarker-guided, risk-adapted surveillance in bladder cancer that reduces unnecessary invasive procedures while maintaining oncologic safety.

Humans↗

PubMed2026

Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression.

BACKGROUND: Genomic analysis has revealed that approximately 40% of bladder cancer (BLCA) tumors harbor alterations in the PI3K/AKT pathway, with PIK3CA mutations occurring in 15-25% of cases. PIK3CA, which encodes the catalytic p110α subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined. METHODS: To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study its effects. We conducted transcriptomic profiling, targeted metabolomics, and stable isotope tracing to assess metabolic reprogramming. Functional assays measured proliferation, mitochondrial complex I activity, and glutaminolysis. Orthotopic xenografts in mice were used to evaluate in vivo tumor growth and metabolism. RESULTS: PIK3CA mutations were present in 20% of cases, consistent with TCGA data. The E545K and E545Q hotspots accounted for 70% of these mutations. PIK3CA E545K strongly activated PI3K/AKT signaling. Transcriptomic analysis revealed enrichment of OXPHOS, fatty acid metabolism, and mTORC1 signaling. Metabolomics indicated changes in TCA cycle metabolites and enhanced reductive carboxylation of glutamine to citrate, driving fatty acid synthesis. Mutant cells showed increased expression of GLS1 and FASN, higher proliferation rates, and elevated mitochondrial complex I activity. In vivo, PIK3CA-mutant xenografts displayed significantly increased tumor growth. CONCLUSION: PIK3CA mutations are frequent drivers of metabolic reprogramming in BLCA, leading to increased glutamine flux, elevated OXPHOS activity, and enhanced fatty acid synthesis, all of which contribute to tumor progression. These findings provide the first comprehensive evidence that PIK3CA-driven metabolic alterations are both biomarkers of aggressive disease and actionable therapeutic targets. The efficacy of PI3Kα inhibition in combination with metabolic targets may support its potential in precision medicine for PIK3CA-mutant BLCA and highlights the value of integrating metabolic biomarkers into treatment strategies for advanced BLCA.

Journal Article↗