The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy

Pancreatic ductal adenocarcinoma (PDAC) has a five‐year survival rate of <4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed high levels of β6 mRNA correlated strongly with significantly poorer survival (n=491 cases, p= 3.17x10‐8). In two separate cohorts we showed that over 80% of PDAC expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration and invasion. Treatment of both αvβ6‐positive human PDAC xenografts and transgenic mice bearing αvβ6‐positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p<0.0001) and increased survival (Log‐rank test, p<0.05). Antibody therapy was associated with suppression of both tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated Caspase 3) and suppression of the pro‐tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA‐positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Potential of biodegradable microneedles as a transdermal delivery vehicle for lidocaine

This article was published in the journal Biotechnology Letters [© Springer Science+Business Media]. The definitive version is available at: http://dx.doi.org/10.1007/s10529-013-1217-3There has been an increasing interest in applying biotechnology in formulating and characterising new and innovative drug delivery methods, e.g., drug-loaded biodegradable microneedles within the area of transdermal delivery technology. Recently, microneedles have been proposed for use in pain management, e.g., post-operative pain management through delivery of a local anaesthetic, namely, lidocaine. Lidocaine is a fairly common, marketed prescription-based, local anaesthetic pharmaceutical, applied for relieving localised pain and lidocaineloaded microneedles have been explored. The purpose of this review is to evaluate the properties of biodegradable polymers that may allow the preparation of microneedle systems, methods of preparing them and pharmacokinetic conditions in considering the potential use of lidocaine for delivery through the skin