Docetaxel is the main treatment for advanced castration‐resistant prostate cancer; however, resistance eventually occurs. The development of intratumoral drug‐resistant subpopulations possessing a cancer stem cell (CSC) morphology is an emerging mechanism of docetaxel resistance, a process driven by epithelial–mesenchymal transition (EMT). This study characterised EMT in docetaxel‐resistant sublines through increased invasion, MMP‐1 production and ZEB1 and ZEB2 expression. We also present evidence for differential EMT across PC‐3 and DU145 in vitro resistance models as characterised by differential migration, cell colony scattering and susceptibility to the CSC inhibitor salinomycin. siRNA manipulation of ZEB1 and ZEB2 in PC‐3 and DU145 docetaxel‐resistant sublines identified ZEB1, through its transcriptional repression of E‐cadherin, to be a driver of both EMT and docetaxel resistance. The clinical relevance of ZEB1 was also determined through immunohistochemical tissue microarray assessment, revealing significantly increased ZEB1 expression in prostate tumours following docetaxel treatment. This study presents evidence for a role of ZEB1, through its transcriptional repression of E‐cadherin to be a driver of both EMT and docetaxel resistance in docetaxel‐resistant prostate cancer. In addition, this study highlights the heterogeneity of prostate cancer and in turn emphasises the complexity of the clinical management of docetaxel‐resistant prostate cancer.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by BCR-ABL1, an oncogenic fusion gene arising from the Philadelphia chromosome. The development of tyrosine kinase inhibitors (TKIs) to overcome the constitutive tyrosine kinase activity of the BCR-ABL protein has dramatically improved disease management and patient outcomes over the past 20 years. However, the majority of patients are not cured and developing novel therapeutic strategies that target epigenetic processes are a promising avenue to improve cure rates. A number of epigenetic mechanisms are altered or reprogrammed during the development and progression of CML, resulting in alterations in histone modifications, DNA methylation and dysregulation of the transcriptional machinery. In this review these epigenetic alterations are examined and the potential of epigenetic therapies are discussed as a means of eradicating residual disease and offering a potential cure for CML in combination with current therapies.

Docetaxel therapy is the gold standard treatment for advanced castrate-resistant prostate cancer (CRPC). However, patients either do not respond or develop resistance over time. Transcriptomic and proteomic analysis of docetaxel-resistant prostate cancer sub-lines developed by our group revealed multiple mechanisms of resistance in line with advanced disease, including over-expression of anti-apoptotic proteins and alterations of NF-KB activation. The sub-lines also demonstrated a coordinated loss and gain of epithelial and mesenchymal markers respectively; a process characteristic of Epithelial-Mesenchymal Transition (EMT). Studies have highlighted a role of EMT in prostate cancer progression, metastasis and docetaxel resistance. However, the role of EMT drivers in mediating resistance is not defined. We hypothesise EMT to be a central mechanism of apoptotic resistance in advanced docetaxel-resistant prostate cancer, representing a target for therapeutic manipulation. EMT was characterised in the PC-3 D12 and DU145 R docetaxel-resistant sub-lines through an increased invasive capacity, MMP-1 secretion and protein expression of E-cadherin transcriptional repressors ZEB1 and ZEB2, in comparison to parental cell lines. This was associated with an increased expression of βIII-tubulin; a tubulin isotype linked to taxane resistance and tumour aggressiveness. Upon treatment with the apoptotic trigger docetaxel (20nM), the PC-3 D12 and DU145 R sub-lines demonstrated significant resistance compared to parental controls. Simultaneous siRNA knockdown of ZEB1 and ZEB2 resulted in both a partial reversal in apoptotic resistance and a decrease in cell viability; this was also associated with a down-regulation of βIII-tubulin and a re-expression of E-cadherin. Our results provide evidence of the process of EMT in in vitro models of docetaxel-resistant prostate cancer, which is associated with differential susceptibility to docetaxel and is partially reversed through siRNA knockdown of the EMT drivers, ZEB1 and ZEB2. In addition, we have identified a link between EMT and βIII-tubulin in our models of docetaxel resistance. Current experiments are investigating the tissue expression of ZEB1 and βIII-tubulin in prostate cancer metastases following docetaxel therapy, which will determine the clinical relevance of EMT and βIII-tubulin as mediators of docetaxel resistance in CRPC. Citation Format: Karen Hanrahan, Maria Prencipe, Jane Bugler, Lisa Murphy, Amanda O'Neill, R. William Watson. The role of ZEB1/ZEB2 and βIII-tubulin in mediating docetaxel-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 730. doi:10.1158/1538-7445.AM2015-730

The International Marine Contractors Association (IMCA) is the international trade association for offshore, marine and underwater engineering companies representing over 1000 member companies worldwide. With its membership actively involved in offshore construction activities primarily for the oil and gas industry, IMCA and its members have been keen to develop appropriate tools to support the industry and drive improvements in safety worldwide. Safety, Environment & Legislation (SEL) is an IMCA core activity. The SEL committee's primary purpose is to promote the sharing of experience and safety and environmental related information among members with the aim of reducing incidents by continuously reinforcing good practice. It also offers good practice guidance to the industry by way of documents, seminars and dialogue. Since 1997 IMCA has been publishing safety flashes from information provided by its members on incidents and potential hazards and lessons learnt from them. This could be faulty equipment, gaps in procedures, reminders of the need for basic safety awareness, and near misses. All safety flashes are available from the IMCA website and the information provided is analyzed to identify trends and whether there is need for industry guidance on topics. The paper will review specific safety flashes and discuss how IMCA has used the information to develop new or review and update its existing guidance. IMCA also collects safety statistics for its contractor members, enabling marine contractors to benchmark their safety performance against other similar sized companies and other stakeholders such as drilling contractors and E&P companies. The paper will highlight some of the trends identified over the last 17 years of data collection, how the data collected has been extended and refined and the recent addition of the collection of environmental information. The paper will explain IMCA's 5 year plan for 2014 to 2019 how the SEL committee has reviewed its work to better define its aims and deliverables to the industry. The paper will discuss how the committee has been restructured to broaden participation from members and drive forward deliverables for the industry.