Nature Reviews Urology最新文献

Diagnostic cystoscopy in combination with transurethral resection of the bladder tumour are the standard for the diagnosis, surgical treatment and surveillance of bladder cancer. The ability to inspect the bladder in its current form stems from a long chain of advances in imaging science and endoscopy. Despite these advances, bladder cancer recurrence and progression rates remain high after endoscopic resection. This stagnation is a result of the heterogeneity of cancer biology as well as limitations in surgical techniques and tools, as incomplete resection and provider-specific differences affect cancer persistence and early recurrence. An unmet clinical need remains for solutions that can improve tumour delineation and resection. Translational advances in enhanced cystoscopy technologies and artificial intelligence offer promising avenues to overcoming the progress plateau.

Prostate-specific membrane antigen (PSMA) is an important cell-surface imaging biomarker and therapeutic target in prostate cancer. The PSMA-targeted theranostic ¹⁷⁷Lu-PSMA-617 was approved in 2022 for men with PSMA-PET-positive metastatic castration-resistant prostate cancer. However, not all patients respond to PSMA-radioligand therapy, in part owing to the heterogeneity of PSMA expression in the tumour. The PSMA regulatory network is composed of a PSMA transcription complex, an upstream enhancer that loops to the FOLH1 (PSMA) gene promoter, intergenic enhancers and differentially methylated regions. Our understanding of the PSMA regulatory network and the mechanisms underlying PSMA suppression is evolving. Clinically, molecular imaging provides a unique window into PSMA dynamics that occur on therapy and with disease progression, although challenges arise owing to the limited resolution of PET. PSMA regulation and heterogeneity - including intertumoural and inter-patient heterogeneity, temporal changes, lineage dynamics and the tumour microenvironment - affect PSMA theranostics. PSMA response and resistance to radioligand therapy are mediated by a number of potential mechanisms, and complementary biomarkers beyond PSMA are under development. Understanding the biological determinants of cell surface target regulation and heterogeneity can inform precision medicine approaches to PSMA theranostics as well as other emerging therapies.

Gene editing technologies help identify the genetic perturbations driving tumour initiation, growth, metastasis and resistance to therapeutics. This wealth of information highlights tumour complexity and is driving cancer research towards precision medicine approaches based on an individual's tumour genetics. Bladder cancer is the 11th most common cancer in the UK, with high rates of relapse and low survival rates in patients with muscle-invasive bladder cancer (MIBC). MIBC is highly heterogeneous and encompasses multiple molecular subtypes, each with different responses to therapeutics. This evidence highlights the need to identify innovative therapeutic targets to address the challenges posed by this heterogeneity. CRISPR-Cas9 technologies have been used to advance our understanding of MIBC and determine novel drug targets through the identification of drug resistance mechanisms, targetable cell-cycle regulators, and novel tumour suppressor and oncogenes. However, the use of these technologies in the clinic remains a substantial challenge and will require careful consideration of dosage, safety and ethics. CRISPR-Cas9 offers considerable potential for revolutionizing bladder cancer therapies, but substantial research is required for validation before these technologies can be used in the clinical setting.

Advancements in imaging modalities have increased the frequency of renal mass discovery. Imaging has typically been considered sufficient to guide management for a large proportion of these tumours, but renal mass biopsies (RMBs) have an increasing role in determining malignancy and can be a valuable tool for preventing unnecessary surgery in patients with benign tumours. A structured approach should be used to help to navigate the expanding repertoire of renal tumours, many of which are molecularly defined. In terms of tumour subtyping, the pathologist's strategy should focus on stratifying patients into clinically different prognostic groups according to our current knowledge of tumour behaviour, including benign, low-grade or indolent, intermediate malignant or highly aggressive. Crucial pathological features and morphological mimicry of tumours can alter the tumour's prognostic group. Thus, pathologists and urologists can use RMB to select patients with tumours at a reduced risk of progression, which can be safely managed with active surveillance within a tailored imaging schedule, versus tumours for which ablation or surgical intervention is indicated. RMB is also crucial in the oncological setting to distinguish between different high-grade tumours and guide tailored management strategies.