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    • AR Vs are truncated AR proteins lacking

    2023-12-15

    AR-Vs are truncated AR proteins lacking the AR ligand-binding domain (AR-LBD) [6]. While AR-Vs have frequently been detected in CRPC, their expression and functional role in benign prostate tissues and primary prostate cancers is not readily apparent. Structural rearrangements in the AR gene and alternative AR mRNA splicing are at least two mechanisms for expression of AR-Vs in CRPC [6]. Multiple AR-Vs arising from AR gene rearrangements and/or alternative splicing have been characterized. To date, AR splice variant-7 (AR-V7) has been studied in greatest detail owing to its relative abundance and frequency of detection in CRPC [7], [8], as well as its potential clinical utility as a marker for treatment selection in men with metastatic CRPC (mCRPC) [9]. However, in-depth studies have also been conducted on other AR-Vs, including AR-V1, AR-V3, AR-V7, AR-V9, and ARv567es [10], [11], [12]. Structural differences of these AR-Vs are illustrated in Figure 1. Since AR-Vs contain the AR DNA-binding domain (DBD) and the AR transcriptional activation domain, they are capable of transcriptional regulation, in spite of the loss of the AR-LBD. Further, since the AR-Vs lack the AR-LBD, they are not regulated by either first-line or novel hormonal therapies currently used in the clinic. At the Mission Androgen Receptor Variants (MARS) 2 meeting, our efforts were streamlined to evaluate the role of AR-Vs as biomarkers, molecular drivers, and therapeutic targets. The authors identified key consensus, discussion points, and critical future work needed to advance the field.
    Evidence acquisition
    Evidence synthesis
    Conclusions
    Introduction Urinary FK506 cancer, which is mostly urothelial carcinoma, is one of the most frequently diagnosed neoplasms, with an estimate of 429,800 new cases and 165,100 deaths occurring in 2012 worldwide (Torre et al., 2015). Despite significant advances in diagnostic technologies as well as surgical techniques and perioperative treatment strategies, the prognosis for bladder cancer remains largely unchanged during the last few decades (Carneiro et al., 2015, Knowles and Hurst, 2015). Indeed, patients with non-muscle-invasive bladder tumor, which generally displays favorable prognosis, still carry a life-long risk of recurrence with occasional progression to muscle invasion following transurethral tumor resection and intravesical pharmacotherapy. Similarly, those with muscle-invasive tumor are at a high risk of developing disease progression and metastasis following more aggressive treatment including radical cystectomy with or without neoadjuvant/adjuvant cisplatin-based systemic chemotherapy. Of note, bladder cancer has been reported to have the highest lifetime costs per patient among all malignancies (Norm et al., 2016, Sievert et al., 2009). Meanwhile, compared with bladder cancer, upper urinary tract urothelial carcinoma is relatively rare, but is often aggressive with poor patient outcomes following nephroureterectomy (Margulis et al., 2009, Raman et al., 2011). In addition, the pathophysiology of upper urinary tract tumors remains poorly understood, although some of molecular or genetic factors are similar to those known to associate with bladder cancer (Catto et al., 2007, Colin et al., 2009). Accordingly, identification of key molecules/pathways responsible for the development and/or progression of urothelial cancer may not only successively provide novel targeted therapy to improve patient outcomes but also contribute to reduction of treatment costs. Men have been at a significantly higher risk than women of developing bladder cancer (Siegel et al., 2017, Torre et al., 2015). Cigarette smoking and exposure to industrial work-related chemicals, such as asbestos, benzidine, and mineral, cutting, or lubricating oil, were well-established risk factors for bladder cancer (Siegel et al., 2015, Siegel et al., 2017, Ugnat et al., 2004) and were thought to contribute to the sex-disparity. However, bladder cancer remains 3–4 times more predominant in men, even after controlling for these carcinogenic factors (Hartge et al., 1990, Hemelt et al., 2009, Siegel et al., 2017). Therefore, intrinsic factors are likely to play a critical role in urothelial carcinogenesis. Meanwhile, emerging preclinical evidence suggests the involvement of androgen receptor (AR) signals in the development and progression of urothelial cancer.