Abstract Context In the past few years, there has been a rapid increase in the number of therapies available to treat metastatic castration-resistant prostate cancer (mCRPC). Currently, approved ...treatments consist of the taxane class of cytotoxic drugs and androgen-targeted therapies. The challenge for clinicians is to decide the best sequence in which to give these therapies to provide the greatest benefit to their patients. Objective To review recent research into the mechanism of action of taxanes in prostate cancer (PCa) cells and the clinical evidence for an interaction between taxanes and androgen-targeted therapies. The implications of these findings for clinical practice are discussed. Evidence acquisition A nonsystematic review of the relevant medical literature between 2004 and the present, in combination with clinical trial data reported at oncology meetings during 2012, was undertaken. Our perspective, focussing on the potential implications for sequencing of therapies for mCRPC, is provided. Evidence synthesis Taxanes are shown to interact with androgen signalling in PCa cells at both the cytoplasmic level (via microtubules) and the nuclear level, affecting transcriptional regulators of androgen-responsive gene expression. Data from clinical trials suggest that androgen deprivation can potentially decrease the efficacy of taxanes in treating PCa. Conclusions These findings have important implications for clinical practice, and there is an urgent need for strong clinical data to support a recommendation for an optimal sequence of therapies.
Summary In 2010, the International Society of Geriatric Oncology (SIOG) developed treatment guidelines for men with prostate cancer who are older than 70 years old. In 2013, a new multidisciplinary ...SIOG working group was formed to update these recommendations. The consensus of the task force is that older men with prostate cancer should be managed according to their individual health status, not according to age. On the basis of a validated rapid health status screening instrument and simple assessment, the task force recommends that patients are classed into three groups for treatment: healthy or fit patients who should have the same treatment options as younger patients; vulnerable patients with reversible impairment who should receive standard treatment after medical intervention; and frail patients with non-reversible impairment who should receive adapted treatment.
Significant progress has been made in the understanding of the underlying cancer biology of castration‐resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining ...implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC.
Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for ...conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.
The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease ...is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts.
We convened a panel of nine clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups.
We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for the interpretation of these variants.
These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.
There is no effective treatment strategy for advanced castration-resistant prostate cancer. Although Docetaxel (Taxotere®) represents the most active chemotherapeutic agent it only gives a modest ...survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. The aims of this study were to further investigate the mechanisms of resistance to Docetaxel. Three Docetaxel resistant sub-lines were generated and confirmed to be resistant to the apoptotic and anti-proliferative effects of increasing concentrations of Docetaxel.
The resistant DU-145 R and 22RV1 R had expression of P-glycoprotein and its inhibition with Elacridar partially and totally reversed the resistant phenotype in the two cell lines respectively, which was not seen in the PC-3 resistant sublines. Resistance was also not mediated in the PC-3 cells by cellular senescence or autophagy but multiple changes in pro- and anti-apoptotic genes and proteins were demonstrated. Even though there were lower basal levels of NF-κB activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher NF-κB activity and IκB phosphorylation at 3 and 6 hours with only minor changes in the DU-145 cells. Inhibition of NF-κB with the BAY 11-7082 inhibitor reversed the resistance to Docetaxel.
This study confirms that multiple mechanisms contribute to Docetaxel resistance and the central transcription factor NF-κB plays an immensely important role in determining docetaxel-resistance which may represent an appropriate therapeutic target.
The progression of benign prostatic hyperplasia (BPH) can be defined as a deterioration of clinical variables such as lower urinary tract symptoms (LUTS), health‐related quality of life and peak flow ...rate, increased prostate size, or unfavourable outcomes such as acute urinary retention (AUR) and BPH‐related surgery. The natural history of BPH is best analysed from longitudinal studies of community‐dwelling men. In the Olmsted county study, which followed for 12 years a randomly selected cohort of 2115 men aged 40–79 years, there was an average increase in the International Prostate Symptom Score (IPSS) of 0.18 points per year, ranging from 0.05 for men in their fifties to 0.44 for those in their seventies. There was also a decrease in peak flow rate of 2% per year and a median prostate growth of 1.9% per year. The cumulative incidence of AUR was low (2.7% over 4 years). Information can also be collected from the placebo arms of controlled studies of men with symptomatic BPH, although the strict trial inclusion criteria and indeed the taking of a placebo itself introduce biases which limit the analysis of the natural history of the disease in this way, and its applicability to the general population. Hence, in the Medical Therapy of Prostatic Symptoms study, there is clear evidence that symptom deterioration, defined by a worsening of the IPSS of ≥ 4 points, was by far the most prevalent progression event (79.5%), with a cumulative incidence of 14% over a mean follow‐up of 4.5 years. As in the longitudinal community‐based studies, AUR was rather uncommon (14.8% of overall progression events) with a cumulative incidence of 2%. BPH‐related surgery, which was a secondary criterion in the study, was required in 5% of men. Similar conclusions can be drawn from a 2‐year placebo‐controlled study (ALTESS) assessing the impact of alfuzosin 10 mg once daily on LUTS/BPH progression in 1522 men with symptomatic BPH at high risk of developing AUR. Symptom deterioration was clearly the main progression event, with a cumulative incidence of 16.8%, compared to BPH‐related surgery (6.5%) and AUR (2.2%). Thus, there is evidence from longitudinal studies, and to a lesser extent from the placebo arms of large controlled studies, that BPH is a progressive disease. Symptom worsening is by far the most frequently occurring progression event. Identifying those patients at risk of BPH progression is crucial to optimize their management.
Abstract The exponential growth of novel therapies for the treatment of metastatic castration-resistant prostate cancer (mCRPC) over the last decade has created an acute need for education and ...guidance of clinicians regarding optimal strategies for patient management. A multidisciplinary panel of 21 European experts in mCRPC assembled for comprehensive discussion and consensus development, seeking to move the field forward and provide guidance and perspectives on optimal selection and sequencing of therapeutic agents and monitoring of response to treatment and disease progression. A total of 110 clinically-relevant questions were addressed and a modified Delphi method was utilised to obtain a consensus. The panel reached a consensus on several important issues, providing recommendations on appropriate phase III clinical trial end-points and optimal strategies for imaging and monitoring of bone metastases. Guidance regarding selection and sequencing of therapy in patients with newly diagnosed or progressive mCRPC is emphasised, including the use of novel bone-targeted agents, chemotherapy, androgen receptor pathway-targeted agents and immunotherapy. The impact of drug resistance and prostate-specific antigen flare on treatment decisions was also addressed. Ultimately, individualised therapy for patients with mCRPC is dependent on continued refinement of clinical decision-making based on patient and disease characteristics. This consensus statement offers clinicians expert guidance on the implementation of recent advances to improve patient outcome, focusing on the future of prostate cancer care.
Regional anesthesia and analgesia attenuate or prevent perioperative factors that favor minimal residual disease after removal of the primary carcinoma. Therefore, the authors evaluated prostate ...cancer recurrence in patients who received either general anesthesia with epidural anesthesia/analgesia or general anesthesia with postoperative opioid analgesia.
In a retrospective review of medical records, patients with invasive prostatic carcinoma who underwent open radical prostatectomy between January 1994 and December 2003 and had either general anesthesia-epidural analgesia or general anesthesia-opioid analgesia were evaluated through October 2006. The endpoint was an increase in postoperative prostate-specific antigen.
After adjusting for tumor size, Gleason score, preoperative prostate-specific antigen, margin, and date of surgery, the epidural plus general anesthesia group had an estimated 57% (95% confidence interval, 17-78%) lower risk of recurrence compared with the general anesthesia plus opioids group, with a corresponding hazard ratio of 0.43 (95% confidence interval, 0.22-0.83; P = 0.012) in a multivariable Cox regression model. Gleason score and tumor size (percent of prostate involved) were also independent predictors of recurrence (hazards ratios of 1.19 1.08, 1.52, P = 0.004, and 1.17 1.03, 1.34 for 10% size difference, P = 0.01, respectively). A similar association between epidural use and recurrence was obtained by comparing patients matched on the propensity to receive epidural versus general anesthesia.
Open prostatectomy surgery with general anesthesia, substituting epidural analgesia for postoperative opioids, was associated with substantially less risk of biochemical cancer recurrence. Prospective randomized trials to evaluate this association seem warranted.
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