Background
Docetaxel, the standard chemotherapy for metastatic castration‐resistant prostate cancer (CRPC) also enhances the survival of patients with metastatic castration‐sensitive prostate cancer ...(CSPC) when combined with androgen‐deprivation therapy. Focal Adhesion Kinase (FAK) activation is a mediator of docetaxel resistance in prostate cancer cells. The aim of this study was to investigate the effect of the second generation FAK inhibitor VS‐6063 on docetaxel efficacy in pre‐clinical CRPC and CSPC models.
Methods
Docetaxel‐resistant CRPC cells, mice with PC3 xenografts, and ex vivo cultures of patient‐derived primary prostate tumors were treated with VS‐6063 and/or docetaxel, or vehicle control. Cell counting, immunoblotting, and immunohistochemistry techniques were used to evaluate the treatment effects.
Results
Docetaxel and VS‐6063 co‐treatment caused a greater decrease in the viability of docetaxel‐resistant CRPC cells, and a greater inhibition in PC3 xenograft growth compared to either monotherapy. FAK expression in human primary prostate cancer was positively associated with advanced tumor stage. Patient‐derived prostate tumor explants cultured with both docetaxel and VS‐6063 displayed a higher percentage of apoptosis in cancer cells, than monotherapy treatment.
Conclusions
Our findings suggest that co‐administration of the FAK inhibitor, VS‐6063, with docetaxel represents a potential therapeutic strategy to overcome docetaxel resistance in prostate cancer.
Docetaxel and cabazitaxel are taxane chemotherapy treatments for metastatic castration-resistant prostate cancer (CRPC). However, therapeutic resistance remains a major issue. MicroRNAs are short ...non-coding RNAs that can silence multiple genes, regulating several signalling pathways simultaneously. Therefore, synthetic microRNAs may have therapeutic potential in CRPC by regulating genes involved in taxane response and minimise compensatory mechanisms that cause taxane resistance. To identify microRNAs that can improve the efficacy of taxanes in CRPC, we performed a genome-wide screen of 1280 microRNAs in the CRPC cell lines PC3 and DU145 in combination with docetaxel or cabazitaxel treatment. Mimics of miR-217 and miR-181b-5p enhanced apoptosis significantly in PC3 cells in the presence of these taxanes. These mimics downregulated at least a thousand different transcripts, which were enriched for genes with cell proliferation and focal adhesion functions. Individual knockdown of a selection of 46 genes representing these transcripts resulted in toxic or taxane sensitisation effects, indicating that these genes may be mediating the effects of the microRNA mimics. A range of these genes are expressed in CRPC metastases, suggesting that these microRNA mimics may be functional in CRPC. With further development, these microRNA mimics may have therapeutic potential to improve taxane response in CRPC patients.
Meta‐Analysis of Cryoablation for AVNRT
Introduction
Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common supraventricular tachycardia referred for ablation. High success rates ...have been accompanied with a small risk of atrioventricular (AV) block. Cryoablation has been used as an alternative to radiofrequency (RF) ablation, but studies have been underpowered in comparing the 2 techniques.
Methods and Results
An electronic search and hand‐search of reference lists for published and unpublished data was carried out. Comparative studies (cohort and randomized controlled trials) of RF versus cryoablation for AVNRT were identified independently by 2 reviewers. Searches were limited to English language human studies. The primary metameter was long‐term AVNRT recurrence (>2 months postprocedure and ECG/electrophysiology study EPS‐documented) and secondary metameters included acute procedural failure and AV block requiring pacing. A total of 5,617 patients in 14 trials were included in this systematic review. Acute procedural failure with cryoablation was slightly higher than with RF ablation, but the difference was not statistically significant (risk ratio RR 1.44 95% confidence interval; CI 0.91–2.28, P = 0.12). Long‐term recurrence was higher with cryoablation (RR 3.66 95% CI 1.84–7.28, P = 0.0002) even after adjusting for larger (6 mm) cryocatheter tips, “insurance lesions” and longer (>6 months) follow‐up duration. RF ablation for AVNRT was associated with permanent AV block in 0.75% of patients, but was not reported in any patients treated with cryoablation (n = 1066, P = 0.01).
Conclusions
Cryoablation is a safe and effective treatment for AVNRT. Although late‐recurrence is more common with cryoablation than with RF ablation, avoidance of permanent AVN block makes it an attractive option in patients where the avoidance of AV block assumes higher priority (such as children and young adults).
Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and ...immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions.
Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20–30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ...ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC.
Lipidomic analysis (∼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1).
Men with elevated circulating ceramide levels had shorter rPFS (HR=2·3, 95% CI=1·5–3·6, p = 0·0004) and shorter OS (HR=2·3, 95% CI=1·4–36, p = 0·0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3·9 vs 8·3 vs 17·7 months; median OS time = 8·9 vs 19·8 vs 34·4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity.
Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors.
None.
Abstract
Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within 12-months. ...There is an urgent need for novel effective therapies for this aggressive tumor. We performed a high-throughput drug screen with over 3,570 biologically active, clinically approved compounds against a panel of neurosphere-forming DIPG cells. We identified 7 compounds - auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine - that were confirmed to have potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells. Using cytotoxicity and clonogenic assays, we found that these drugs were able to inhibit DIPG-neurosphere proliferation and colony formation in vitro. To determine whether the in vitro efficacy could be replicated in vivo, we tested the activity of each of these compounds in an orthotopic DIPG model. Of the agents tested, fenretinide, auranofin and SAHA were the most active anti-tumor agents, significantly enhancing the survival of tumor bearing animals. Mechanistic studies showed fenretinide enhancing apoptotic cell death of DIPG cells via inhibition of PDGFRa transcription and downregulation of the PI3K/AKT/MTOR pathway. We therefore examined the therapeutic efficacy of fenretinide using a second orthotopic model with PDGFRa amplification. We used two different fenretinide formulations which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG.
Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most devastating of all brain tumours. They mostly affect young children and, as there are no effective treatments, almost all will die of their ...tumour within 12 months. We performed a high throughput screen (HTS) of 3500 clinically available compounds, which identified fenretinide among the top 33 most active agents against DIPG. In an attempt to find novel combination therapies, which could enhance the cytotoxic efficacy of fenretinde we performed a combination HTS based on the remaining 32 agents together with 50 chemotherapeutic agents against fenretinide. This approach identified drugs that enhanced fenretinide activity including Ion channel inhibitors (ivermectin, halofantrine, diphenylhydantoin), neurotransmitter receptor antagonist (GR-127935), receptor tyrosine kinases (RTKs) inhibitors (ponatinib, pazopanib) and histone deacetylase (HDAC) inhibitor saha. These promising 7 combinations were selected for further investigation in vitro using cytotoxicity assays, colony formation assays, while the best combination was further validated by flow cytometry assessing apoptotic events and western blotting to elucidate mechanisms of action. When tested against a panel of four neurosphere forming DIPG cultures, only ponatinib was found to uniformly enhance the anti-proliferative effects of fenretinide. Colony formation assays showed that fenretinide combined with ponatinib, pazopanib, GR127935, and diphenylhydantoin led to significantly reduced colony formation both with and without irradiation. Flow cytometric analysis enhanced apoptotic events in the combination treated cells. Furthermore we found that although fenretinide combination inhibited the PDGFR/PI3K pathway, these effects didn’t appear to be mediated at the gene expression level. In vivo experiments examining the therapeutic efficacy of fenretinide/irradiation and ponatinib combinations are currently undergoing using an orthotopic model of DIPG. Preliminary results indicate that delivery of fenretinide with irradiation could extend the survival of mice. This novel and potentially effective DIPG treatment strategy is readily translatable to clinical trial.
Abstract
DIPGs are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within 12 months. There is an urgent need for novel ...effective therapies for this aggressive tumor. We performed a high-throughput drug screen with over 3,500 biologically active, clinically approved compounds against a panel of neurosphere-forming DIPG cells. We identified 7 compounds- auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine- that were confirmed to have potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells. Using cytotoxicity and clonogenic assays, we found that these drugs were able to inhibit DIPG-neurosphere proliferation and colony formation in-vitro. To determine whether the in-vitro efficacy could be replicated in-vivo, we tested the activity of each of these compounds in an orthotopic DIPG model. Of the agents tested, fenretinide and SAHA were the most active anti-tumor agents, significantly enhancing the survival of tumor bearing animals. Mechanistic studies showed fenretinide enhancing apoptotic cell death of DIPG cells via inhibition of PDGFRa transcription and downregulation of the PI3K/AKT/MTOR pathway. We therefore examined the therapeutic efficacy of fenretinide using a second orthotopic model with PDGFRa amplification. We used two different Fenretinide formulations (LYM-X-Sorb and NanoMicelle) which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG.
Dysregulated lipid metabolism is associated with more aggressive pathology and poorer prognosis in prostate cancer (PC). The primary aim of the study is to assess the relationship between the plasma ...lipidome and clinical outcomes in localised and metastatic PC. The secondary aim is to validate a prognostic circulating 3-lipid signature specific to metastatic castration-resistant PC (mCRPC).
Comprehensive lipidomic analysis was performed on pre-treatment plasma samples from men with localised PC (N = 389), metastatic hormone-sensitive PC (mHSPC)(N = 44), or mCRPC (validation cohort, N = 137). Clinical outcomes from our previously published mCRPC cohort (N = 159) that was used to derive the prognostic circulating 3-lipid signature, were updated. Associations between circulating lipids and clinical outcomes were examined by Cox regression and latent class analysis.
Circulating lipid profiles featuring elevated levels of ceramide species were associated with metastatic relapse in localised PC (HR 5.80, 95% CI 3.04-11.1, P = 1 × 10
), earlier testosterone suppression failure in mHSPC (HR 3.70, 95% CI 1.37-10.0, P = 0.01), and shorter overall survival in mCRPC (HR 2.54, 95% CI 1.73-3.72, P = 1 × 10
). The prognostic significance of circulating lipid profiles in localised PC was independent of standard clinicopathological and metabolic factors (P < 0.0002). The 3-lipid signature was verified in the mCRPC validation cohort (HR 2.39, 95% CI 1.63-3.51, P = 1 × 10
).
Elevated circulating ceramide species are associated with poorer clinical outcomes across the natural history of PC. These clinically actionable lipid profiles could be therapeutically targeted in prospective clinical trials to potentially improve PC outcomes.
Airline websites are expected to become the major channel for flight bookings in the coming decade. Unlike e-commerce websites, airline products are intangible and complex, with varying sales ...conditions attached. This study aimed at testing the usability of two types of flight search information presentation styles— a text-based and a graphic-based interface—via flight booking experiments in a laboratory environment. Results showed that the graphic-based interface could improve flight booking accuracy with higher user satisfaction. The graphic-based interface was found to be able to reduce flight booking time when the flight booking scenario was simple but was not able to help when a complex flight booking scenario was presented. The graphic-based interface also improved web page browsing efficiency by reducing eye-fixation duration. In addition, users' personal factors, such as booking experience and learning styles, were found to have a significant influence on users’ mental effort during the flight selection stage of booking.
•Two different flight information presentation styles are studied for online air ticket booking.•We measured the usability by incorporating an eye-tracker and EGG in experiments.•Graphic-based interface was found to improve flight booking accuracy.•Graphic-based interface enhanced user satisfaction.•Graphic-based interface improved browsing efficiency when the itinerary is simple.
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