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The poor bioavailability of various drugs is the utmost obstacle in oral drug delivery. The use of natural bioenhancer as supplements with the primary therapeutic agent has gained wider acceptance and has been emerged as a potential method to increase the bioavailability of various drugs. Gallic acid is one of the chief phenolic natural compounds extensively distributed in plants and fruit. Despite its broad spectrum pharmacological effects, gallic acid significantly augments the bioavailability of diverse classes of drugs at low doses by impeding liver metabolism and altering gastrointestinal permeability. In this context, this review aims to summarise the promising bioavailability enhancing activity of gallic acid on different therapeutic agents. Furthermore, current evidence confirms that the intervention with gallic acid leads to enhance the bioavailability of various drugs; however, extensive research is need of the hour so that it could be utilized in drug formulations in the future for clinical use.

Supplementary Figure 2 (Relates to Figure 2) - SIK2 knock-down reduces proliferation and viability of LNCaP-Bic, C4-2 and DuCaP cells.

Supplementary Figure 1 (Relates to Figure 2) - Kinase-dead SIK2 and SIK2 knock-down reduce proliferation of LNCaP cells.

Supplementary Figure 7 (Relates to Figure 6) - Validation of microarray hits.

Supplementary Figure Legend

Supplementary Table S1. qRT-PCR primer sequences. When primer sequences were not from published studies, they were designed using Integrated DNA Technologies software.

Supplementary Figure 4 (Relates to Figure 4) - SIK2 localises at the centrosomes of SKOv3 and LNCaP cells.

Supplementary Figure 6 (Relates to Figure 5) - SIK2 regulates CREB1 activity via the phosphorylation of TORC2 and TORC3 and their sequestration in the cytoplasm.

Supplementary Figure 5. Validation of SIK2, TORC1, TORC2 and TORC3 antibodies by Western-Blot.

Supplementary Figure 8 (Relates to Figure 6) - SIK2 regulates a cell cycle network and a ER stress network related to cancer.

Supplementary Figure 3 (Relates to Figure 4) - SIK2 knock-down induces a cell cycle arrest in G1 phase and delays mitotic progression of LNCaP cells.

Traditional medicinal plants have wide-reaching utilisation in the treatment of diabetes especially in developing countries where medical resources are meagre. Traditionally used anti-diabetic plants act by numerous mechanisms, however, only a few of them act through activation of the glucokinase enzyme. Glucokinase is a key regulatory enzyme in glucose metabolism thereby controls glucose homeostasis and insulin secretion. The present review significantly analyses the knowledge about various plant-based glucokinase activators including numerous phytochemicals which modulate the activity and gene expression of glucokinase and would provide data support and perspective regarding future research in the discovery and development of different plant-derived glucokinase activators.

Background: Benzothiazole is an organosulfur heterocyclic compound that has a considerable place in drug discovery due to significant pharmacological actions. Objective: The main objective of the present study was to synthesize some novel 2-(5-substituted 1,3,4-oxadiazole-2-yl)-1,3-benzothiazole derivatives and evaluate them for their anticonvulsant activity using in silico and in vivo methods. Methods: A set of sixteen 2-(5-substituted 1, 3, 4-oxadiazole-2-yl)-1, 3-benzothiazole derivatives were prepared using multi-step reactions starting from o-amino-thiophenol and characterized by suitable spectral techniques. The synthesized compounds were evaluated for anticonvulsant activity using in silico and in vivo methods. In silico molecular docking study was performed using Molegro Virtual Docker software to analyze binding modes of compounds with the internal ligand of PDB ID: 1OHY and 1OHV; and in vivo pharmacological activities were tested for both generalized tonic-clonic seizures and generalized absence (petit mal) seizures using Maximal Electrical Shock and PTZ-induced seizure models, respectively. Results: Some new 2-(5-substituted-1,3,4-oxadiazole-2-yl)-1,3- benzothiazole (5a-5p) were successfully synthesized by finally refluxing 1, 3-benzothiazole-2-carboxyhydrazide with different aromatic acids in phosphoryl chloride. Docking results showed that compounds 5c, 5j, and 5m were found to have the highest number of H-bond interactions; i.e. 4, 4, and 7 respectively with target proteins 1OHY and 6, 3, and 4 respectively with target protein 1OHV, whereas phenytoin showed only two H-bonding with both proteins. In the Maximal electroshock seizure method, the synthesized compounds 5h, 5k and 5o demonstrated potent anticonvulsant activity against the tonic seizure with a significant decrease in tonic hind leg extension period with a mean duration of 7.9, 7.4, and 7.0 sec respectively, as compared to the other synthesized compounds. In contrast, in the PTZ-induced seizure model, compounds 5c, 5h, and 5m showed protection against clonic convulsion with significant elevation in the onset time of clonic convulsion at 311.2, 308.0, and 333.11 sec, respectively. Conclusion: Thus, from the results, it can be concluded that compound 5h, a benzothiazole derivative endowed with an oxadiazole ring, can be developed as a potential anticonvulsant agent.

Heterocyclic compounds with thiazole moiety are one of the most promising compounds in the medicinal chemistry possessing numerous therapeutic activities. The present was designed to study the high throughput in silico screening of 10 designed 2-phenyl-amino thiazole derivatives as a potent FABH inhibitor in Molegro virtual docker software (Version 6.0) using 3iL9 as PDB. The docking results showed mol dock score of -90.94 with four hydrogen bonding for the standard drugs griseofulvin, while on the other hand, N-substituted thiazole derivatives S2, S5, S6, S7, S8, and S9 exhibited excellent mol dock score, ranged from -102.612 to -144.236, hydrogen bonding (4-10), and docking score ranged from -104.873 to -143.593. Similarly, another in silico study was done using online PASS software and the compounds S1, S2, S5, S6, S7, S8, and S9 have Pa ranged between 0.310 to 0.411 and showed good antibacterial activity whereas, compounds having Pa ranged between 0.216 to 0.334 demonstrated potent antifungal activity when compared to standard drugs. Thus, the present study affirmed the significant antimicrobial potential of some designed N-substituted thiazole derivatives based on their mol dock values and other parameters when studies in silico and the obtained results will provide data support and offer perspectives in future researches to develop potent antimicrobial agents from these N-substituted thiazole derivatives.

A highly selective, sensitive, and fast HPLC based bioanalytical method was developed and validated for the estimation of atorvastatin in rat plasma which can be further employed in pharmacokinetic studies. The developed analytical procedure utilized protein precipitation approach to extract atorvastatin from rat plasma using ice-cold acetonitrile as an extraction solvent and diclofenac as IS. The chromatographic separation of atorvastatin was achieved on a LiChrospher RP C-18 column (250 × 4.6 mm, 5 μm) using isocratic elution of Methanol: water (containing 0.05 % glacial acetic acid) (70:30, v/v pH 3.0) as mobile phase with 1mL min-1flow rate and further detected by UV absorbance at 248 nm. Atorvastatin eluted within 3.093 min, whereas IS eluted at 8.953 min. The developed method was validated as per USFDA guidelines. Linearity was observed in concentration between 15.62 ng mL-1to 2000 ng mL-1with r2equals to 0.9999 and LOQ 10.45 ng mL-1. The developed method follows the all acceptance criteria concerning its linearity, accuracy, precision, selectivity, dilution integrity, and recovery. Also, atorvastatin was demonstrated to be stable in the battery of stability studies such as freeze-thaw, bench-top, autosampler, short-term, and long-term stability. Thus the developed bioanalytical assay can be used in pharmacokinetic studies.&nbsp

Benzothiazole is one of the promising heterocyclic compounds in the medicinal chemistry, endowed with several therapeutic potentials. The present research endeavors the high throughputin silicoscreening of 66 designed benzothiazole derivatives as potent GABA-aminotransferase inhibitors in Molegro virtual docker software (Version 6.0) using 1OHV as PDB. The docking results showed mol dock score of -73.63 and -62.45 for the standard drugs phenytoin and carbamazepine respectively, on the other hand, the benzothiazole derivatives SDZ3, SDZ4, SDZ5, SDZ6, SDZ13, SDZ16, SDZ19, SDZ21, SDZ32, SDZ51, and SDZ64 exhibited excellent mol dock score, ranged from -104.23 to -121.56. Apart from mol dock score, excellent hydrogen bonding with amino acids of PDB was observed in most of the studied compounds. Compound SDZ4, SDZ8, SDZ11, SDZ31, SDZ57, SDZ58, SDZ59, SDZ60, SDZ61, SDZ63, SDZ64, SDZ65, and SDZ66 showed 5 to 7 hydrogen bond interactions, however, the standard drug phenytoin showed H-bond interaction with 2 amino acid; N-Glu109 and N-Asn110 with bond length 2.86 Å and 3.10 Å respectively, and 2 interaction with N-Asn110 and O-Cys47 with bond length 3.00 Å, and 3.35 Å respectively were observed in carbamazepine. Thus, the present study affirmed the significant anticonvulsant potential of some designed benzothiazole derivatives based on their mol dock values and other parameters when studiesin silicoand the obtained results will provide data support and offer perspectives in future researches to develop a potent anticonvulsant agent from these benzothiazole derivatives.

We have previously reported that the negative signaling regulator Similar Expression to FGF (hSef) is downregulated in prostate cancer and its loss is associated with clinical metastasis. Here, we explored the mechanistic basis of this finding. We first confirmed our clinical observation by testing hSef manipulation in an in vivo metastasis model. hSef stable expressing cells (PC3M‐hSef) or empty vector controls (PC3M‐EV) were injected subcutaneously into the lateral thoracic walls of NOD‐SCID gamma mice and lungs were harvested at autopsy. In this model, 6/7 PC3M‐EV xenografts had definitive lung micro‐metastasis whilst only 1/6 PC3M‐hSef xenografts exhibited metastasis recapitulating the clinical scenario (p = 0.03). Gene expression studies revealed key perturbations in genes involved in cell motility and epithelial to mesenchymal transition (EMT) along with alterations in cognate signaling pathways. These results were validated in an EMT specific PCR array whereby hSef over‐expression and silencing reciprocally altered E‐Cadherin expression (p =, What's new? The loss of negative signaling regulators may be implicated in prostate cancer metastasis, but the underlying mechanisms remain unclear. Here, by using a combination of xenograft, gene expression microarray, phosphokinase array and quantitative PCR techniques, the authors provide first evidence that the negative regulator hSef plays a key role in regulating epithelial to mesenchymal transition (EMT) in prostate cancer, which in turn results in changes in the metastatic ability of tumor cells. The results support the notion that the expression levels of hSef and other negative signaling regulators may be key biomarkers for the identification of triggers for metastasis.

We aimed to determine short-term patient-reported outcomes in men having general anesthetic transperineal (TP) prostate biopsies. A prospective cohort study was performed in men having a diagnostic TP biopsy. This was done using a validated and adapted questionnaire immediately post-biopsy and at follow-up of between 7 and 14 days across three tertiary referral hospitals with a response rate of 51.6%. Immediately after biopsy 43/201 (21.4%) of men felt light-headed, syncopal, or suffered syncope. Fifty-three percent of men felt discomfort after biopsy (with 95% scoring

Objective: To determine the incidence of prostatic urethral involvement in our patient population and how prostatic urethral biopsy correlates with final cystectomy pathology. Patients and methods: We conducted a retrospective review of prostatic urethral biopsies (PUB) performed between February 2008 and April 2012 in a single centre. PUB pathology was correlated with cystectomy pathology. Results: PUB was undergone by 172 patients with a median age of 70 years (range: 37–84 years): There were 35 (20%) patients having a positive PUB and 137 (80%) who were negative. Of the 94 patients who underwent cystectomy, we found that when the entire prostatic urethra was sectioned, 20 (21%) patients had cancer in the prostatic urethra. Cancer was found in 17 (77%) of 22 patients with a positive PUB and in three (4%) out of the 72 with a negative PUB (positive predictive value (PPV) 77%, negative predictive value (NPV) 96%, sensitivity 85% and specificity 93%). In all 94 patients, the prostatic apical margin was negative. Conclusion: Disease in the prostatic urethra affected 20% of patients, consistent with published data. Prostatic urethral apical margins were all negative. Intra-operative frozen section would have missed cancer in the 20 patients with prostatic urethral cancer, whereas PUB identified 17 (85%) of the 20 patients. These data confirm the value of using PUB before cystectomy, in our UK population.

Background Prostate biopsy supported by transperineal image fusion has recently been developed as a new method to the improve accuracy of prostate cancer detection. Objective To describe the Ginsburg protocol for transperineal prostate biopsy supported by multiparametric magnetic resonance imaging (mpMRI) and transrectal ultrasound (TRUS) image fusion, provide learning points for its application, and report biopsy results. The article is supplemented by a Surgery in Motion video. Design, setting, and participants This single-centre retrospective outcome study included 534 patients from March 2012 to October 2015. A total of 107 had no previous prostate biopsy, 295 had benign TRUS-guided biopsies, and 159 were on active surveillance for low-risk cancer. Surgical procedure A Likert scale reported mpMRI for suspicion of cancer from 1 (no suspicion) to 5 (cancer highly likely). Transperineal biopsies were obtained under general anaesthesia using BiopSee fusion software (Medcom, Darmstadt, Germany). All patients had systematic biopsies, two cores from each of 12 anatomic sectors. Likert 3–5 lesions were targeted with a further two cores per lesion. Outcome measurements and statistical analysis Any cancer and Gleason score 7–10 cancer on biopsy were noted. Descriptive statistics and positive predictive values (PPVs) and negative predictive values (NPVs) were calculated. Results and limitations The detection rate of Gleason score 7–10 cancer was similar across clinical groups. Likert scale 3–5 MRI lesions were reported in 378 (71%) of the patients. Cancer was detected in 249 (66%) and Gleason score 7–10 cancer was noted in 157 (42%) of these patients. PPV for detecting 7–10 cancer was 0.15 for Likert score 3, 0.43 for score 4, and 0.63 for score 5. NPV of Likert 1–2 findings was 0.87 for Gleason score 7–10 and 0.97 for Gleason score ≥4+3=7 cancer. Limitations include lack of data on complications. Conclusions Transperineal prostate biopsy supported by MRI/TRUS image fusion using the Ginsburg protocol yielded high detection rates of Gleason score 7–10 cancer. Because the NPV for excluding Gleason score 7–10 cancer was very high, prostate biopsies may not be needed for all men with elevated prostate-specific antigen values and nonsuspicious mpMRI. Patient summary We present our technique to sample (biopsy) the prostate by the transperineal route (the area between the scrotum and the anus) to detect prostate cancer using a fusion of magnetic resonance and ultrasound images to guide the sampling.

New technologies for the detection of prostate cancer are emerging regularly. The authors summarise recent advances in prostate cancer diagnostics, including serum, urine and tissue markers, and outline improvements in imaging and biopsy techniques.

To determine the accuracy of multiparametric magnetic resonance imaging (mpMRI) during the learning curve of radiologists using MRI targeted, transrectal ultrasonography (TRUS) guided transperineal fusion biopsy (MTTP) for validation.Prospective data on 340 men who underwent mpMRI (T2-weighted and diffusion-weighted MRI) followed by MTTP prostate biopsy, was collected according to Ginsburg Study Group and Standards for Reporting of Diagnostic Accuracy standards. MRI data were reported by two experienced radiologists and scored on a Likert scale. Biopsies were performed by consultant urologists not 'blinded' to the MRI result and men had both targeted and systematic sector biopsies, which were reviewed by a dedicated uropathologist. The cohorts were divided into groups representing five consecutive time intervals in the study. Sensitivity and specificity of positive MRI reports, prostate cancer detection by positive MRI, distribution of significant Gleason score and negative MRI with false negative for prostate cancer were calculated. Data were sequentially analysed and the learning curve was determined by comparing the first and last group.We detected a positive mpMRI in 64 patients from Group A (91%) and 52 patients from Group E (74%). The prostate cancer detection rate on mpMRI increased from 42% (27/64) in Group A to 81% (42/52) in Group E (P0.001). The prostate cancer detection rate by targeted biopsy increased from 27% (17/64) in Group A to 63% (33/52) in Group E (P0.001). The negative predictive value of MRI for significant cancer (Gleason 3+3) was 88.9% in Group E compared with 66.6% in Group A.We demonstrate an improvement in detection of prostate cancer for MRI reporting over time, suggesting a learning curve for the technique. With an improved negative predictive value for significant cancer, decision for biopsy should be based on patient/surgeon factors and risk attributes alongside the MRI findings.

Background To assess if transperineal prostate (TP) biopsy affects th e outcome of robotic-assisted laparoscopic prostatectomy (RALP), with particular reference to perioperative complications, oncological results and functional outcomes in the early postoperative setting. Methods We identified 61 men who had undergone RALP after TP biopsies, from June 2012 to June 2014 and a control group of 120 men who had undergone RALP after conventional TRUS biopsy in the same period. Data was compared from the pre-operative biopsy, peri- and postoperative period, procedural outcomes including histological, oncological and functional outcomes between the groups. Results The groups had comparable demographics, with matched median ages and PSA levels. There was a higher incidence of Gleason 6 disease detected in the TRUS group (P=0.01). Mean operative time (146 minutes TRUS vs. 158 minutes TP, P=0.133), blood loss (250 mL TRUS vs. 288 mL TP, P=0.462) and intraoperative complications were not significantly different between groups. Median length of stay (1 day) and median catheter duration (7 days) were identical in both cohorts. PSA failure rate at 6 months was similar (11.7% TRUS vs. 9.8% TP, P=0.904). There were no differences in functional outcomes (potency or continence) between groups at 6 month s follow-up. Conclusions RALP is safe after TP biopsy with no adverse impact on oncological or short-term functional outcomes.

Objectives To define terms and processes and agree on a minimum dataset in relation to transperineal prostate biopsy procedures and enhanced prostate diagnostics. To identify the need for further evaluation and establish a collaborative research practice. Patients and Methods A 19-member multidisciplinary panel rated 66 items for their appropriateness and their definition to be incorporated into the international databank using the Research and Development/University of California Los Angeles Appropriateness Method. The item list was developed from interviews conducted with healthcare professionals from urology, radiology, pathology and engineering. Results The panel agreed on 56 items that were appropriate to be incorporated into a prospective database. In total, 10 items were uncertain and were omitted. These items were within the categories: definitions (n = 2), imaging (n = 1), surgical protocols (n = 2) and histology (n = 5). Conclusions The components of a minimum dataset for transperineal prostate biopsy have been defined. This provides an opportunity for multicentre collaborative data analysis and technique development. The findings of the present study will facilitate prospective studies into the application and outcome of transperineal prostate biopsies.

Live kidney donation is becoming increasingly common as the need for donors is unmet from the deceased donor population. However, there are potential risks to the donor, and careful counselling and rigorous pretransplant assessment are imperative. The authors discuss the ethical implications associated with live organ donation. Copyright © 2013 John Wiley & Sons

Introduction: We characterized false negative prostate magnetic resonance imaging (MRI) reporting by using histology derived from MRI-transrectal ultrasound (TRUS)-guided transperineal (MTTP) fusion biopsies.Methods: In total, 148 consecutive patients were retrospectively reviewed. Men underwent multiparametric MRI (mpMRI), reported by a consultant/attending radiologist in line with European Society of Urogenital Radiology (ESUR) standards. MTTP biopsy of the lesions was performed according to the Ginsburg recommendations. Cases with an MRI-histology mismatch were identified and underwent a second read by an experienced radiologist. A third review was performed with direct histology comparison to determine a true miss from an MRI-occult cancer. Statistical analysis was performed with McNemar’s test.Results: False negative lesions were identified in 29 MRI examinations (19.6%), with a total of 46 lesions. Most false negative lesions (21/46) were located in the anterior sectors of the prostate. The second read led to a significant decrease of false-negative lesions with 7/29 further studies identified as positive on a patientby- patient basis (24.1% of studies, p = 0.016) and 11/46 lesions (23.9%; p = 0.001). Of these, 30 lesions following the first read and 23 lesions after the second read were considered significant cancer according to the University College London criteria. However, on direct comparison with histology, most lesions were MRI occult.Conclusion: We demonstrate that MRI can fail to detect clinically relevant lesions. Improved results were achieved with a second read but despite this, a number of lesions remain MRI-occult. Further advances in imaging are required to reduce false negative results.

Salt-inducible kinase 2 (SIK2) is a multifunctional kinase of the AMPK family that plays a role in CREB1-mediated gene transcription and was recently reported to have therapeutic potential in ovarian cancer. The expression of this kinase was investigated in prostate cancer clinical specimens. Interestingly, auto-antibodies against SIK2 were increased in the plasma of patients with aggressive disease. Examination of SIK2 in prostate cancer cells found that it functions both as a positive regulator of cell-cycle progression and a negative regulator of CREB1 activity. Knockdown of SIK2 inhibited cell growth, delayed cell-cycle progression, induced cell death, and enhanced CREB1 activity. Expression of a kinase-dead mutant of SIK2 also inhibited cell growth, induced cell death, and enhanced CREB1 activity. Treatment with a small-molecule SIK2 inhibitor (ARN-3236), currently in preclinical development, also led to enhanced CREB1 activity in a dose- and time-dependent manner. Because CREB1 is a transcription factor and proto-oncogene, it was posited that the effects of SIK2 on cell proliferation and viability might be mediated by changes in gene expression. To test this, gene expression array profiling was performed and while SIK2 knockdown or overexpression of the kinase-dead mutant affected established CREB1 target genes; the overlap with transcripts regulated by forskolin (FSK), the adenylate cyclase/CREB1 pathway activator, was incomplete. Implications: This study demonstrates that targeting SIK2 genetically or therapeutically will have pleiotropic effects on cell-cycle progression and transcription factor activation, which should be accounted for when characterizing SIK2 inhibitors. Mol Cancer Res; 13(4); 620–35. ©2014 AACR.

Karan Wadhwa, Raj Singh, Lemke Z SolomonDepartment of Urology, Queen Alexandra Hospital, Portsmouth, UKAbstract: A 69-year-old man presented with sudden onset of macroscopic hematuria. While an ultrasound of the bladder revealed a posterior bladder mass, subsequent flexible cystoscopy demonstrated only an area of irregular urothelium. Initial general anesthetic cytoscopy and biopsy revealed conventional G2/3 T1 TCC. Histology of a further formal resection of this irregular area revealed carcinoma-in-situ and population of atypical cells with enlarged nuclei, prominent nucleoli, and varying quantities of cytoplasm showing plasma cell features. The immunohistochemistry was consistent with a plasmacytoma. There must be a high index of suspicion when ultrasound demonstrates a mass not detected by flexible cystoscopy, and biopsies/resection are advised to exclude extramedullary plasmacytoma (EMP) as the cause. EMP of the urinary bladder is a rare entity with only 21 cases reported in the literature. In this report we describe a further case of EMP of the bladder associated with synchronous transitional cell carcinoma (TCC) of the urothelium. We also highlight the important histopathological findings and review the current literature to report the outcomes of existing approaches to management of this rare form of bladder cancer. We believe this to be the first case reported in which a patient presented concurrently with bladder EMP and urothelial TCC. EMPs are highly radiosensitive tumors and in the case of head/neck disease, survival at 10 years is in the order of 65% following radical radiotherapy. Given the paucity of reported cases of primary bladder EMP, the optimal treatment regime remains unclear. In keeping with other anatomical sites current treatment is based to the assumed benefit of radical radiotherapy and prognosis appears to be better in those with no evidence of systemic disease.Keywords: bladder cancer, extramedullary plasmacytoma, urothelial transitional cell carcinoma

Background: Medical therapy for men with prostate cancer (PCa) is evolving, including recent evidence to support the use of chemotherapy for men with hormone sensitive disease. PI3K/AKT/mTOR pathway aberrations are common in patients with primary PCa and almost universal in metastatic tumours. The mTOR pathway acts as a central regulator of tumour cell metabolism, proliferation, cell cycle progression and immune regulation. The aim of this study was to investigate the effects of mTOR inhibitor AZD2014 on tumour growth and immune infiltration in a genetically engineered mouse model of PCa. Methods: PtenL/L;PB-Cre4 mice, which developed invasive hormone-sensitive prostate tumours between 10-14 months of age, were enrolled (n = 13-15 per group) and treated with AZD2014 (15mg/Kg) or vehicle orally for 14 doses (QD 5/7) with or without castration. Tumour volumes were assessed by ultrasound imaging. Tumour samples were collected within 4 hours post 14th dose for histological and molecular analysis. Results: AZD2014 was well tolerated, no overt toxicity was observed. Mean plasma concentrations of AZD2014 were 4.4±2.1μM at time of tumour sampling. AZD2014 alone or AZD2014+castration inhibited mTORC1 and mTORC2 activity as demonstrated by reduced p4EBP1(Thr37/46) 48%±27% (P Conclusion: These data confirm the anti cancer effect of AZD2014 in this PCa model. Furthermore, AZD2014+castration was more effective than either treatment as a single agent. The increased intra-tumoral T cell infiltration observed may have contributed to the anti-tumour effect. Further studies are ongoing to maximise this therapeutic effect and will inform current clinical studies in men with hormone sensitive, high risk prostate cancer. Citation Format: Chiranjeevi Sandi, Antonio Ramos-Montoya, Sergio L. Filisbino, Adina Hughes, Suzanne Mosely, Michelle Morrow, Robert W. Wilkinson, Sarah Jurmeister, Karan Wadhwa, Frances M. Richards, Duncan I. Jodrell, Sabina Cosulich, Barry R. Davies, Simon Pacey. The dual mTOR inhibitor, AZD2014, and castration increase intra-tumoral immune cell infiltration and anti-tumour activity in a genetically engineered mouse model of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 389.

Clinical studies have shown the improved benefit of combining androgen deprivation therapy (ADT) with radiotherapy, indicating a potential interaction between the androgen signalling and DNA damage response (DDR) pathways in PCa. We have explored the underlying basis of this interaction by interrogating the mechanism of androgen regulation of the DDR in men with PCa, both untreated and treated with an androgen inhibitor. We show that androgen receptor (AR) signalling regulates the DDR and promotes DDR foci formation leading to ATM activation in PCa. Our data showing that AR regulates DDR provides an explanation for the improved outcome of combined ADT and radiotherapy. Thus, our work identifies the rationale for targeting both the AR and DDR pathways simultaneously to improve therapy outcome in advanced or high risk prostate cancer. Citation Format: Mohammad Asim, Heather Zecchini, Firas Tarish, Charlie Massie, Ajoeb Baridi, Anne Warren, Wanfeng Zhao, Leigh-Anne McDuffus, Patrice Mascalchi, Greg Shaw, Harveer Dev, Karan Wadhwa, Paul Wijnhoven, Josep Forment, Scott Lyons, Andy Lynch, Cormac O’Neill, Vincent Zecchini, Paul Rennie, Aria Baniahmad, Simon Tavare, Ian Mills, Niklas Schulz, Yaron Galanty, Thomas Helleday, David Neal. The human androgen receptor regulates DNA damage response (DDR) in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-176.

Background: An estimated 220,800 cases and 27,540 deaths from prostate cancer (PCa) will occur in the USA during 2015. Altered PI3K/AKT/mTOR signalling contributes to prostate cancer progression and transition to androgen-independent disease, for example one study reported 42% of primary and 100% of metastatic PCa tumours exhibited mutations, altered expression or copy number variations within this pathway. First generation mTOR inhibitors (preferentially inhibit mTORC1), have had limited anti-cancer effect in patients with PCa, possibly due to negative feedback activation of the AKT pathway via mTORC2. The dual mTORC1/2 inhibitor, AZD2014, may overcome this liability. Using a genetically engineered PTEN conditional mouse model (Ptenloxp/loxp;PB-Cre4), we have investigated the effects of AZD2014. The studies complement a clinical trial (NCT02064608) of AZD2014, given to men before radical prostatectomy and are timed for when invasive prostate carcinomas develop in the model around 10-14 months prior to onset of resistance to castration through AKT pathway activation. AZD2014, 15mg/kg daily, oral (with or without castration) or vehicle were administered for 14 days. Results: AZD2014 was well tolerated with no overt toxicity observed. Pharmacokinetic (PK) analysis revealed mean concentrations of 4.4±2.1μM of AZD2014 in the plasma samples collected 4 hours after day 14 dose. AZD2014 alone or combined with castration inhibited mTORC1 and mTORC2 measured by reductions in p4EBP1(Thr37/46) by approximately 48%±27% (p Conclusions: Short term (14 days) treatment with AZD2014 with or without castration was associated with both pharmacodynamic and anti-tumour effects. The t-Cho/Cr ratio, previously reported as positively correlated with Gleason score in PCa patients, might be, in addition to our standard mTOR PD markers, utilised as a non-invasive biomarker of AZD2014 activity. The primary and phenotypic biomarker effects of monotherapy with AZD2014 in this relevant genetically engineered mouse model of prostate cancer will be compared with paired biopsies from the ongoing exploratory window study in the prostate cancer patients prior to prostatectomy, and may inform potential novel combination approaches that are translatable to the clinic. Citation Format: Chiranjeevi Sandi, Antonio Ramos-Montoya, Sergio L. Felisbino, Sarah Jurmeister, Basetti Madhu, Karan Wadhwa, John R. Griffiths, Frances M. Richards, Duncan I. Jodrell, David E. Neal, Sabina Cosulich, Barry Davies, Simon Pacey. Preclinical evaluation of dual mTOR inhibitor, AZD2014, in prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A123.

PURPOSE: To compare histological outcomes in patients undergoing MRI-transrectal ultrasound fusion transperineal (MTTP) prostate biopsy and determine the incremental benefit of targeted cores. METHODS: Seventy-six consecutive patients with 89 MRI-identified targets underwent MTTP biopsy. Separate targeted biopsies and background cores were obtained according to a standardized protocol. Target biopsies were considered of added diagnostic value if these cores showed a higher Gleason grade than non-targeted cores taken from the same sector (Group 1, n = 41). Conversely, where background cores demonstrated an equal or higher Gleason grade, target cores were considered to be non-beneficial (Group 2, n = 48). RESULTS: There was no significant difference in age, PSA, prostate volume, time-to-biopsy, and number of cores obtained between the groups. A greater proportion of target cores were positive for cancer (158/228; 69.3 %) compared to background (344/1881; 18.38 %). The median target volume was 0.54 cm(3) for Group 1 (range 0.09-2.79 cm(3)) and 1.65 cm(3) for Group 2 (0.3-9.07 cm(3)), p < 0.001. The targets in Group 1 had statistically lower diameters for short and long axes, even after correction for gland size. The highest area under the receiver operating characteristic curve was demonstrated when a lesion cutoff value of 1.0 cm in short axis was applied, resulting in a sensitivity of 83.3 % and a specificity of 82.9 %. CONCLUSIONS: When a combined systematic and targeted transperineal prostate biopsy is performed, there is limited benefit in acquiring additional cores from larger-volume targets with a short axis diameter >1.0 cm.