Epitranscriptomic mechanisms of androgen signalling and prostate cancer.

Prostate cancer (PCa) is the second most common cancer diagnosed in men. While radical prostatectomy and radiotherapy are often successful in treating localised disease, post-treatment recurrence is common. As the androgen receptor (AR) and androgen hormones play an essential role in prostate carcinogenesis and progression, androgen deprivation therapy (ADT) is often used to deprive PCa cells of the pro-proliferative effect of androgens. ADTs act by either blocking androgen biosynthesis (e.g. abiraterone) or blocking AR function (e.g. bicalutamide, enzalutamide, apalutamide, darolutamide). ADT is often effective in initially suppressing PCa growth and progression, yet emergence of castrate-resistant PCa and progression to neuroendocrine-like PCa following ADT are major clinical challenges. For this reason, there is an urgent need to identify novel approaches to modulate androgen signalling to impede PCa progression whilst also preventing or delaying therapy resistance. The mechanistic convergence of androgen and epitranscriptomic signalling offers a potential novel approach to treat PCa. The epitranscriptome involves covalent modifications of mRNA, notably, in the context of this review, the N(6)-methyladenosine (m6A) modification. m6A is involved in the regulation of mRNA splicing, stability, and translation, and has recently been shown to play a role in PCa and androgen signalling. The m6A modification is dynamically regulated by the METTL3-containing methyltransferase complex, and the FTO and ALKBH5 RNA demethylases. Given the need for novel approaches to treat PCa, there is significant interest in new therapies that target m6A that modulate AR expression and androgen signalling. This review critically summarises the potential benefit of such epitranscriptomic therapies for PCa patients.

Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles.

Prostate cancer (PCa) is a leading male malignancy worldwide, often progressing to bone metastasis, with limited curative options. Extracellular vesicles (EVs) have emerged as key players in cancer communication and metastasis, promoting the formation of supportive microenvironments in distant sites. Our previous studies have highlighted the role of PCa EVs in modulating osteoblasts and facilitating tumor progression. However, the early pre-metastatic changes induced by PCa EVs within the bone microenvironment remain poorly understood. To investigate the early effects of repeated exposure to PCa EVs in vivo, mimicking EVs being shed from the primary tumor, PCa EVs isolated from cell line PC3MLuc2a were fluorescently labelled and repeatedly administered via tail vein injection to adult CD1 NuNu male mice for a period of 4 weeks. In vivo imagining, histological analysis and gene expression profiling were performed to assess the impact of PCa EVs on the bone microenvironment. We demonstrate for the first time that PCa EVs home to both bone and lymph nodes following repeated exposures. Furthermore, the accumulation of EVs within the bone leads to distinct molecular changes indicative of disrupted bone homeostasis (e.g., changes to signaling pathways such as Paxillin p = 0.0163, Estrogen Receptor p = 0.0271, RHOA p = 0.0287, Ribonucleotide reductase p = 0.0307 and ERK/MAPK p = 0.0299). Changes in key regulators of these pathways were confirmed in vitro on human osteoblasts. In addition, our data compares the known gene signature of osteocytes and demonstrates a high proportion of overlap (52.2%), suggesting a potential role for this cell type in response to PCa EV exposure. No changes in bone histology or immunohistochemistry were detected, indicating that PCa EV mediated changes were induced at the molecular level. This study provides novel insights into the alterations induced by PCa EVs on the bone microenvironment. The observed molecular changes indicate changes in key pathways and suggest a role for osteocytes in these EV mediated early changes to bone. Further research to understand these early events may aid in the development of targeted interventions to disrupt the metastatic cascade in PCa.

Salbutamol for analgesia in renal colic: study protocol for a prospective, randomised, placebo-controlled phase II trial (SARC).

BACKGROUND: Renal colic is the pain experienced by a patient when a renal calculus (kidney stone) causes partial or complete obstruction of part of the renal outflow tract. The standard analgesic regimes for renal colic are often ineffective; in some studies, less than half of patients achieve complete pain relief, and a large proportion of patients require rescue analgesia within 4 h. Current analgesic regimes are also associated with significant side effects including nausea, vomiting, drowsiness and respiratory depression. It has been hypothesised that beta adrenoreceptor agonists, such as salbutamol, may reduce the pain of renal colic. They have been shown to impact a number of factors that target the physiological causes of pain in renal colic (ureteric spasm and increased peristalsis, increased pressure at the renal pelvis and prostaglandin release with inflammation). There is biological plausibility and a body of evidence sufficient to suggest that this novel treatment for the pain of renal colic should be taken to a phase II clinical trial. The aim of this trial is to test whether salbutamol is an efficacious analgesic adjunct when added to the standard analgesic regime for patients presenting to the ED with subsequently confirmed renal colic. METHODS: A phase II, randomised, placebo-controlled trial will be performed in an acute NHS Trust in the East Midlands. Patients presenting to the emergency department with pain requiring IV analgesia and working diagnosis of renal colic will be randomised to receive standard analgesia ± a single intravenous injection of Salbutamol. Secondary study objectives will explore the feasibility of conducting a larger, phase III trial. DISCUSSION: The trial will provide important information about the efficacy of salbutamol as an analgesic adjunct in renal colic. It will also guide the development of a definitive phase III trial to test the cost and clinical effectiveness of salbutamol as an analgesic adjunct in renal colic. Salbutamol benefits from widespread use across the health service for multiple indications, extensive staff familiarity and a good side effect profile; therefore, its potential use for pain relief may have significant benefits for patient care. TRIAL REGISTRATION: ISRCTN Registry ISRCTN14552440 . Registered on 22 July 2019.

KI67 and DLX2 predict increased risk of metastasis formation in prostate cancer-a targeted molecular approach.

BACKGROUND: There remains a need to identify and validate biomarkers for predicting prostate cancer (CaP) outcomes using robust and routinely available pathology techniques to identify men at most risk of premature death due to prostate cancer. Previous immunohistochemical studies suggest the proliferation marker Ki67 might be a predictor of survival, independently of PSA and Gleason score. We performed a validation study of Ki67 as a marker of survival and disease progression and compared its performance against another candidate biomarker, DLX2, selected using artificial neural network analysis. METHODS: A tissue microarray (TMA) was constructed from transurethral resected prostatectomy histology samples (n=192). Artificial neural network analysis was used to identify candidate markers conferring increased risk of death and metastasis in a public cDNA array. Immunohistochemical analysis of the TMA was carried out and univariate and multivariate tests performed to explore the association of tumour protein levels of Ki67 and DLX2 with time to death and metastasis. RESULTS: Univariate analysis demonstrated Ki67 as predictive of CaP-specific survival (DSS; P=0.022), and both Ki67 (P=0.025) and DLX2 (P=0.001) as predictive of future metastases. Multivariate analysis demonstrated Ki67 as independent of PSA, Gleason score and D'Amico risk category for DSS (HR=2.436, P=0.029) and both Ki67 (HR=3.296, P=0.023) and DLX2 (HR=3.051, P=0.003) as independent for future metastases. CONCLUSIONS: High Ki67 expression is only present in 6.8% of CaP patients and is predictive of reduced survival and increased risk of metastasis, independent of PSA, Gleason score and D'Amico risk category. DLX2 is a novel marker of increased metastasis risk found in 73% patients and 8.2% showed co-expression with a high Ki67 score. Two cancer cell proliferation markers, Ki67 and DLX2, may be able to inform clinical decision-making when identifying patients for active surveillance.

3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors.

There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor-derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non-small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753-63. ©2016 AACR.

MicroRNA in prostate cancer: functional importance and potential as circulating biomarkers.

BACKGROUND: This non-systematic review article aims to summarise the progress made in understanding the functional consequences of microRNA (miRNA) dysregulation in prostate cancer development, and the identification of potential miRNA targets as serum biomarkers for diagnosis or disease stratification. RESULTS: A number of miRNAs have been shown to influence key cellular processes involved in prostate tumourigenesis, including apoptosis-avoidance, cell proliferation and migration and the androgen signalling pathway. An overlapping group of miRNAs have shown differential expression in the serum of patients with prostate cancer of varying stages compared with unaffected individuals. The majority of studies thus far however, involve small numbers of patients and have shown variable and occasionally conflicting results CONCLUSION: MiRNAs show promise as potential circulating biomarkers in prostate cancer, but larger prospective studies are required to validate particular targets and better define their clinical utility.

Very high residual volumes should not prevent transurethral resection of the prostate being offered to men presenting with urinary retention.

OBJECTIVE: The aim of this study was to identify factors at presentation that can help to predict outcomes and guide subsequent management decisions in patients with acute on chronic retention. MATERIAL AND METHODS: The medical notes of 187 consecutive patients presenting with urinary retention at two teaching hospitals between 2008 and 2009 were reviewed. All patients were followed up for a minimum of 3 years. All patients were catheterized at presentation. The majority then underwent one or more of trial without catheter (TWOC), transurethral resection of the prostate (TURP) (both considered successful if the patient voided with a subsequent postvoid residual volume of <200 ml on three successive occasions) or long-term catheterization. Patient factors such as age, associated acute kidney injury (AKI), performance status, residual volume, prior lower urinary tract symptoms (LUTS), treatment of LUTS, diagnosis of diabetes and neuropathy were recorded. RESULTS: Increasing age (p = 0.002) and increasing residual volume (p = 0.046) were associated with a significant increase in the failure of TWOC. The rate of AKI increased significantly with residual volume (p < 0.0001). As residual volume increased so did the likelihood that a patient would undergo TURP (p = 0.0009). Age did not appear to influence the outcome of TURP (p = 0.17). Increasing residual volume did not significantly reduce the likelihood of successful TURP (p = 0.068). CONCLUSIONS: High residual volumes should not preclude TURP. There is a clear correlation between AKI and residual volume. Increasing age and residual volume both reduce the likelihood of successful TWOC.

Update on the management of T1 renal cortical tumours.

There are a range of treatment strategies for the management of patients with small incidental renal cortical tumours including active surveillance, radiofrequency ablation, cryotherapy, radical nephrectomy and partial nephrectomy. A large number of such tumours are benign and might therefore be over-treated with radical nephrectomy. There are emergent short-term oncological and clinical outcomes for cryotherapy and radiofrequency ablation, and recent studies have illustrated the benefits of partial nephrectomy for minimizing the risk of progression to chronic kidney disease. The outcomes of these different treatment methods are discussed.

Mammalian target of rapamycin: a new target in prostate cancer.

Molecular targets in prostate cancer are continually being explored, especially in the poor-prognosis androgen-independent phase of the disease, for which there are currently few therapeutic options. One such target is the mammalian target of rapamycin (mTOR) protein. Activation of mTOR results in sequential activation of downstream molecules, which ultimately results in cell division. In this review, we consider the rationale for pursuing mTOR as a therapeutic target in prostate cancer and summarize preclinical and clinical studies of mTOR inhibition in prostate cancer.

Resveratrol--a prostate cancer chemopreventive agent?

The incidence of prostate cancer in Western countries continues to rise. Whilst opinion remains divided on the best treatment for localized disease, intervention for metastatic, hormone-independent cancer remains extremely limited. The concept of chemoprevention is gaining popularity as an effective means of reducing the burden of prostate cancer on the population, and many compounds with putative chemopreventive activity are currently under investigation. Resveratrol is a plant-derived polyphenolic compound which has a wide spectrum of biological activity. It has anti-oxidant and anti-inflammatory properties, and may induce apoptosis as well as modulate the function of the androgen receptor in prostate cancer cell lines. Further studies to evaluate the use of this compound as a chemopreventive agent in prostate cancer are warranted.