Targeting EMT in cancer: opportunities for pharmacological intervention

•EMT is important for embryonic development, wound healing, and placentation. •Some cancers appear to exploit this process for increased metastatic potential. •Therefore, this pathway is of great therapeutic interest in the treatment of cancer. The spread of cancer cells to distant organs represents a major clinical challenge in the treatment of cancer. Epithelial–mesenchymal transition (EMT) has emerged as a key regulator of metastasis in some cancers by conferring an invasive phenotype. As well as facilitating metastasis, EMT is thought to generate cancer stem cells and contribute to therapy resistance. Therefore, the EMT pathway is of great therapeutic interest in the treatment of cancer and could be targeted either to prevent tumor dissemination in patients at high risk of developing metastatic lesions or to eradicate existing metastatic cancer cells in patients with more advanced disease. In this review, we discuss approaches for the design of EMT-based therapies in cancer, summarize evidence for some of the proposed EMT targets, and review the potential advantages and pitfalls of each approach

Targeting glucocorticoid receptors that promote resilience in the treatment of addiction

There is strong evidence to suggest that the combination of alcohol and chronic repetitive stress leads to long-lasting effects on brain function, specifically areas associated with stress, motivation and decision-making such as the amygdala, nucleus accumbens and prefrontal cortex. Alcohol and stress together facilitate the imprinting of long-lasting memories. The molecular mechanisms and circuits involved are being studied but are not fully understood. Current evidence suggests that corticosterone (animals) or cortisol (humans), in addition to direct transcriptional effects on the genome, can directly regulate pre- and postsynaptic synaptic transmission through membrane bound glucocorticoid receptors (GR). Indeed, corticosterone-sensitive synaptic receptors may be critical sites for stress regulation of synaptic responses. Direct modulation of synaptic transmission by corticosterone may contribute to the regulation of synaptic plasticity and memory during stress (Johnson et al., 2005; Prager et al., 2010). Specifically, previous data has shown that long term alcohol (1) increases the expression of NR2Bcontaining NMDA receptors at glutamate synapses, (2) changes receptor density, and (3) changes morphology of dendritic spines (Prendergast and Mulholland; 2012). During alcohol withdrawal these changes are associated with increased glucocorticoid signalling and increased neuronal excitability. It has therefore been proposed that these synapse changes lead to the anxiety and alcohol craving associated with withdrawal (Prendergast and Mulholland; 2012). My lab is targeting this receptor system and the amygdala in order to understand the effect of combining alcohol and stress on these pathways. Lastly, we are testing GR specific compounds as potential new medications to promote the development of resilience to developing addiction.

Targeting Antiapoptotic Genes Upregulated by Androgen Withdrawal Using Antisense Oligodeoxynucleotides to Enhance Androgen-and Chemo-Sensitivity in Prostate Cancer

Androgen withdrawal is the only effective form of systemic therapy for men with advanced disease, producing symptomatic and/or objective response in 80% of patients. Unfortunately, androgen independent (AI) progression and death occurs within a few years in the majority of these cases (6). Prostate cancer is highly chemoresistant, with objective response rates of 10% and no demonstrated survival benefit (28). Hormone refractory prostate cancer (HRPC) is therefore the main obstacle to improving the survival and quality of life in patients with advanced disease, and novel therapeutic strategies that target the molecular basis of androgen and chemoresistance are required.

Initial prototype testing of Ray's Night Out: A new mobile app targeting risky drinking in young people

Background Risky single occasion drinking (RSOD; 4 or more drinks in <6 h) more than doubles the risk of injury in young people (15 - 25 years). The potential role of smartphone apps in reducing RSOD in young people is yet to be explored. Objective: To describe the initial prototype testing of ‘Ray's Night Out’, a new iPhone app targeting RSOD in young people. Method Quantitative and qualitative methods were used to evaluate the quality, perceived utility, and acceptability of the app among nine young people (19e23 years). Results Participants reported Ray's Night Out had good to excellent levels of functionality and visual appeal, acceptable to good levels of entertainment, interest and information, and acceptable levels of customization and interactivity. Young people thought the app had high levels of youth appeal, would prompt users to think about their alcohol use limits, but was unlikely to motivate a change in alcohol use in its current form. Qualitative data provided several suggestions for improving the app. Conclusion Following revision, Ray's Night Out could provide an effective intervention for RSOD in non help-seeking young people. A randomized controlled trial is currently underway to test the final prototype of the app.

Truckies and workplace health promotion: Targeting a hard-to-reach group

- Introduction Research identifies truck drivers as being at high risk of chronic disease. For most truck drivers their workplace is their vehicle. Truck drivers’ health is impacted by the limitations of this unique working environment, including reduced opportunities for physical activity and the intake of healthy foods. Workplaces are widely recognised as effective platforms for health promotion. However, the effectiveness of traditional and contemporary health promotion interventions in truck drivers’ novel workplace is unknown. - Methods This project worked with six transport industry workplaces in Queensland, Australia over a two-year period. Researchers used Participatory Action Research (PAR) processes to engage truck drivers and workplace managers in the implementation and evaluation of six workplace health promotion interventions. These interventions were designed to support truck drivers to increase their physical activity and access to healthy foods at work. They included traditional health promotion interventions such as a free fruit initiative, a ten thousand steps challenge, personal health messages and workplace posters, and a contemporary social media intervention. Participants were engaged via focus groups, interviews and mixed-methods surveys. - Results The project achieved positive changes in truck drivers’ health knowledge and health behaviours, particularly related to nutrition. There were positive changes in truck drivers’ self-reported health rating, body mass index (BMI) and readiness to make health-related lifestyle changes. There were also positive changes in truck drivers reporting their workplace as a key source of health information. These changes were underpinned by a positive shift in the culture of participating workplaces. Truck drivers’ perceptions of their workplace valuing, encouraging, modelling and facilitating healthy nutrition and physical activity behaviours improved. PAR processes enabled researchers to develop relationships with workplace managers, contextualise interventions and deliver rigorous outcomes. Despite the novelty of truck drivers’ mobile workplace, traditional health promotion interventions were more effective than contemporary ones. - Conclusion In this workplace health promotion project targeting a ‘hard-to-reach’ group of truck drivers, a combination of well-designed traditional workplace interventions and the PAR process resulted in positive health outcomes.

Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function

Memory T cells develop early during the preclinical stages of autoimmune diseases and have traditionally been considered resistant to tolerance induction. As such, they may represent a potent barrier to the successful immunotherapy of established autoimmune diseases. It was recently shown that memory CD8+ T cell responses are terminated when Ag is genetically targeted to steady-state dendritic cells. However, under these conditions, inactivation of memory CD8+ T cells is slow, allowing transiently expanded memory CD8+ T cells to exert tissue-destructive effector function. In this study, we compared different Ag-targeting strategies and show, using an MHC class II promoter to drive Ag expression in a diverse range of APCs, that CD8+ memory T cells can be rapidly inactivated by MHC class II+ hematopoietic APCs through a mechanism that involves a rapid and sustained downregulation of TCR, in which the effector response of CD8+ memory cells is rapidly truncated and Ag-expressing target tissue destruction is prevented. Our data provide the first demonstration that genetically targeting Ag to a broad range of MHC class II+ APC types is a highly efficient way to terminate memory CD8+ T cell responses to prevent tissue-destructive effector function and potentially established autoimmune diseases. Copyright © 2010 by The American Association of Immunologists, Inc.

Evaluation of polymeric nanomedicines targeted to PSMA: Effect of ligand on targeting efficiency

Targeted nanomedicines offer a strategy for greatly enhancing accumulation of a therapeutic within a specific tissue in animals. In this study, we report on the comparative targeting efficiency toward prostate-specific membrane antigen (PSMA) of a number of different ligands that are covalently attached by the same chemistry to a polymeric nanocarrier. The targeting ligands included a small molecule (glutamate urea), a peptide ligand, and a monoclonal antibody (J591). A hyperbranched polymer (HBP) was utilized as the nanocarrier and contained a fluorophore for tracking/analysis, whereas the pendant functional chain-ends provided a handle for ligand conjugation. Targeting efficiency of each ligand was assessed in vitro using flow cytometry and confocal microscopy to compare degree of binding and internalization of the HBPs by human prostate cancer (PCa) cell lines with different PSMA expression status (PC3-PIP (PSMA+) and PC3-FLU (PSMA−). The peptide ligand was further investigated in vivo, in which BALB/c nude mice bearing subcutaneous PC3-PIP and PC3-FLU PCa tumors were injected intravenously with the HBP-peptide conjugate and assessed by fluorescence imaging. Enhanced accumulation in the tumor tissue of PC3-PIP compared to PC3-FLU highlighted the applicability of this system as a future imaging and therapeutic delivery vehicle.

Targeting neuropilin-1 to inhibit prostate cancer invasion and metastasis

Recent reports provide evidence that the epithelial-to-mesenchymal transition (EMT) plays a key role in prostate cancer (PCa) metastasis and therapy resistance. We have recently identified the cell surface receptor, Neuropilin-1 (NRP1) to be increased during epithelial-mesenchymal transition (EMT) and this study aims to determine whether the inhibition of NRP1 will be a feasible therapeutic strategy for blocking PCa metastasis and therapy resistance.

Targeting the fibroblast growth factor receptor family in cancer

Fibroblast growth factors (FGFs) regulate a plethora of biological functions, in both the embryonic and adult stages of development, binding their cognate receptors and thus activating a variety of downstream signalling pathways. Deregulation of the FGF/FGFR signalling axis, observed in multifarious tumor types including squamous non-small cell lung cancer, occurs through genomic FGFR alterations that drive ligand-independent receptor signalling or alterations that support ligand-dependent activation. Mutations are not restricted to the tyrosine kinase domain and aberrations appear to be tumor type dependent. As well as its complementarity and synergy with VEGF of particular interest is the interplay between FGFR and EGFR and the ability of these pathways to offer a compensatory signalling escape mechanism when either is inhibited. Hence there exists a rationale for a combinatorial approach to inhibition of these dysregulated pathways to reverse drug resistance. To date, several multi-target tyrosine kinase inhibitors as well as FGFR specific tyrosine kinase inhibitors (TKIs), monoclonal antibodies and FGF ligand traps have been developed. Promising preclinical data has resulted in several drugs entering clinical trials. This review explores aberrant FGFR and its potential as a therapeutic target in solid tumors.

VEGF-mediated cell survival in non-small-cell lung cancer: implications for epigenetic targeting of VEGF receptors as a therapeutic approach

Aims: To evaluate the potential therapeutic utility of histone deacetylase inhibitors (HDACi) in targeting VEGF receptors in non-small-cell lung cancer. Materials & methods: Non-small-cell lung cancer cells were screened for the VEGF receptors at the mRNA and protein levels, while cellular responses to various HDACi were examined. Results: Significant effects on the regulation of the VEGF receptors were observed in response to HDACi. These were associated with decreased secretion of VEGF, decreased cellular proliferation and increased apoptosis which could not be rescued by addition of exogenous recombinant VEGF. Direct remodeling of the VEGFR1 and VEGFR2 promoters was observed. In contrast, HDACi treatments resulted in significant downregulation of the Neuropilin receptors. Conclusion: Epigenetic targeting of the Neuropilin receptors may offer an effective treatment for lung cancer patients in the clinical setting.

Response and damage evaluation of reinforced concrete frames subjected to blast loading

Bomb attacks carried out by terrorists, targeting high occupancy buildings, have become increasingly common in recent times. Large numbers of casualties and property damage result from overpressure of the blast followed by failing of structural elements. Understanding the blast response of multi-storey buildings and evaluating their remaining life have therefore become important. Response and damage analysis of single structural components, such as columns or slabs, to explosive loads have been examined in the literature, but the studies on blast response and damage analysis of structural frames in multi-storey buildings is limited and this is necessary for assessing the vulnerability of them. This paper investigates the blast response and damage evaluation of reinforced concrete (RC) frames, designed for normal gravity loads, in order to evaluate their remaining life. Numerical modelling and analysis were carried out using the explicit finite element software, LS DYNA. The modelling and analysis takes into consideration reinforcement details together and material performance under higher strain rates. Damage indices for columns are calculated based on their residual and original capacities. Numerical results generated in the can be used to identify relationships between the blast load parameters and the column damage. Damage index curve will provide a simple means for assessing the damage to a typical multi-storey building RC frame under an external bomb circumstance.

A cluster-randomised intervention trial against Schistosoma japonicum in the Peoples' Republic of China: bovine and human transmission

Background Zoonotic schistosomiasis japonica is a major public health problem in China. Bovines, particularly water buffaloes, are thought to play a major role in the transmission of schistosomiasis to humans in China. Preliminary results (1998–2003) of a praziquantel (PZQ)-based pilot intervention study we undertook provided proof of principle that water buffaloes are major reservoir hosts for S. japonicum in the Poyang Lake region, Jiangxi Province. Methods and Findings Here we present the results of a cluster-randomised intervention trial (2004–2007) undertaken in Hunan and Jiangxi Provinces, with increased power and more general applicability to the lake and marshlands regions of southern China. The trial involved four matched pairs of villages with one village within each pair randomly selected as a control (human PZQ treatment only), leaving the other as the intervention (human and bovine PZQ treatment). A sentinel cohort of people to be monitored for new infections for the duration of the study was selected from each village. Results showed that combined human and bovine chemotherapy with PZQ had a greater effect on human incidence than human PZQ treatment alone. Conclusions The results from this study, supported by previous experimental evidence, confirms that bovines are the major reservoir host of human schistosomiasis in the lake and marshland regions of southern China, and reinforce the rationale for the development and deployment of a transmission blocking anti-S. japonicum vaccine targeting bovines.