Systems approach for the selection of micro-RNAs as therapeutic biomarkers of anti-EGFR monoclonal antibody treatment in colorectal cancer.

miRNA plays an important role in tumourgenesis by regulating expression of oncogenes and tumour suppressors. Thus affects cell proliferation and differentiation, apoptosis, invasion and angiogenesis. miRNAs are potential biomarkers for diagnosis, prognosis and therapies of different forms of cancer. However, relationship between response of cancer patients towards targeted therapy and the resulting modifications of the miRNA transcriptome in the context of pathway regulation is poorly understood. With ever-increasing pathways and miRNA-mRNA interaction databases, freely available mRNA and miRNA expression data in multiple cancer therapy have produced an unprecedented opportunity to decipher the role of miRNAs in early prediction of therapeutic efficacy in diseases. Efficient translation of -omics data and accumulated knowledge to clinical decision-making are of paramount scientific and public health interest. Well-structured translational algorithms are needed to bridge the gap from databases to decisions. Herein, we present a novel SMARTmiR algorithm to prospectively predict the role of miRNA as therapeutic biomarker for an anti-EGFR monoclonal antibody i.e. cetuximab treatment in colorectal cancer.

Molecular biomarkers in clinical development: what could we learn from the clinical trial registry?

AIM: Objective of this research is to assess whether the trend of stratified medicine widely discussed in scientific literature is translated into real clinical trials registered in ClinicalTrials.gov . METHODS: By semi-automatic screening of over 150,000 trials, we filtered trials with stratified biomarker to analyze their therapeutic focus, major drivers and elucidated the impact of stratified biomarker programs on trial duration and completion. RESULTS: >5% of trials are using molecular biomarker for stratification; duration of such trials is longer. 21% of them are done in late stages and Oncology is the major focus. CONCLUSION: Trials with stratified biomarker in drug development has quadrupled in last decade but represents a small part of all interventional trials reflecting multiple co-developmental challenges of therapeutic compounds and companion diagnostics.

Challenges and opportunities of drug repositioning.

Drug repositioning is an innovation stream of pharmaceutical development that offers advantages for drug developers along with safer medicines for patients. Several drugs have been successfully repositioned to a new indication, with the most prominent of them being viagra and thalidomide, which have generated historically high revenues. In line with these developments, most of the recent articles and reviews on repositioning are focused on success stories, leaving behind the challenges that repositioned compounds have on the way to the clinic. Here, I analyze repositioning as a business opportunity for pharmaceutical companies, weighing both challenges and opportunities of repositioning. In addition, I suggest extended profiling as a lower-risk cost-effective repositioning model for pharmaceutical companies and elucidate the novel collaborative business opportunities that help to realize repositioning of shelved and marketed compounds.

Challenges and opportunities for oncology biomarker discovery.

Recent success of companion diagnostics along with the increasing regulatory pressure for better identification of the target population has created an unprecedented incentive for drug discovery companies to invest in novel strategies for biomarker discovery. In parallel with the rapid advancement and clinical adoption of high-throughput technologies, a number of knowledge management and systems biology approaches have been developed to analyze an ever increasing collection of OMICs data. This review discusses current biomarker discovery technologies highlighting challenges and opportunities of knowledge capturing and presenting a perspective of the future integrative modeling approaches as an emerging trend in biomarker prediction.

Mining biomarker information in biomedical literature.

BACKGROUND: For selection and evaluation of potential biomarkers, inclusion of already published information is of utmost importance. In spite of significant advancements in text- and data-mining techniques, the vast knowledge space of biomarkers in biomedical text has remained unexplored. Existing named entity recognition approaches are not sufficiently selective for the retrieval of biomarker information from the literature. The purpose of this study was to identify textual features that enhance the effectiveness of biomarker information retrieval for different indication areas and diverse end user perspectives. METHODS: A biomarker terminology was created and further organized into six concept classes. Performance of this terminology was optimized towards balanced selectivity and specificity. The information retrieval performance using the biomarker terminology was evaluated based on various combinations of the terminology's six classes. Further validation of these results was performed on two independent corpora representing two different neurodegenerative diseases. RESULTS: The current state of the biomarker terminology contains 119 entity classes supported by 1890 different synonyms. The result of information retrieval shows improved retrieval rate of informative abstracts, which is achieved by including clinical management terms and evidence of gene/protein alterations (e.g. gene/protein expression status or certain polymorphisms) in combination with disease and gene name recognition. When additional filtering through other classes (e.g. diagnostic or prognostic methods) is applied, the typical high number of unspecific search results is significantly reduced. The evaluation results suggest that this approach enables the automated identification of biomarker information in the literature. A demo version of the search engine SCAIView, including the biomarker retrieval, is made available to the public through http://www.scaiview.com/scaiview-academia.html. CONCLUSIONS: The approach presented in this paper demonstrates that using a dedicated biomarker terminology for automated analysis of the scientific literature maybe helpful as an aid to finding biomarker information in text. Successful extraction of candidate biomarkers information from published resources can be considered as the first step towards developing novel hypotheses. These hypotheses will be valuable for the early decision-making in the drug discovery and development process.

Discovery of a novel tumour metastasis-promoting gene, NVM-1.

We have previously reported that over-expression of a panel of 119 genes correlates with the metastatic potential of pancreatic carcinoma cells. We sought to identify and functionally characterize candidate tumour metastasis promoting genes among this library using a secondary phenotype-assisted screen. Here we report the discovery of the metastasis-promoting function of a hitherto not characterized gene located on chromosome 14 (ORF138), which we have named 'novel metastasis-promoting gene 1' (NVM-1). The NVM-1 transcript is extensively alternatively spliced, is expressed endogenously in a number of different tissues, and is strongly over-expressed at the protein level in a variety of human tumour types. Importantly, NVM-1 expression stimulates the migratory and invasive behaviour of tumour cells and promotes metastasis formation in experimental animals in vivo. Up-regulation of FMNL2 and MT1E and down-regulation of TIMP4 and MHC-I is observed as a consequence of NVM-1 expression. Together these data identify NVM-1 as a gene that is functionally involved in tumour metastasis, and suggest that NVM-1 may constitute a promising therapeutic target for inhibition of tumour metastasis.

Competition between glucocorticoid receptor and NFkappaB for control of the human FasL promoter.

Glucocorticoids mediate a variety of biological effects via binding their intracellular receptor. Ligand-bound glucocorticoid receptor (GR) translocates to the nucleus and regulates gene transcription in a DNA binding-dependent or independent manner. The predominant biological effect of glucocorticoids on peripheral T cells is immunosupression via transcriptional repression of genes induced during T cell activation. Glucocorticoids have been implicated in the inhibition of activation-induced T cell apoptosis by virtue of their down-regulation of Fas ligand (fasL) expression. It is believed that FasL, similar to other cytokines, is repressed by glucocorticoids via GR interaction with other transcription factors, interfering with their transactivation ability. Here, we show that human fasL is directly regulated by GR in a DNA binding-dependent manner. A negative GR element found at position -990 in the fasL promoter binds GR in vitro as well as in the chromatin context. This negative glucocorticoid response element overlaps with a known NFkappaB binding site. GR down-regulates fasL promoter by competing with NFkappaB for binding to the common response element. Thus, fasL is the first gene described whose repression by GR is mediated by sterical occlusion of NFkappaB DNA binding. This type of repression represents an additional mechanism for the GR-NFkappaB mutual antagonism.

SUMOylation of the corepressor N-CoR modulates its capacity to repress transcription.

In the absence of ligands the corepressor N-CoR mediates transcriptional repression by some nuclear hormone receptors. Several protein-protein interactions of N-CoR are known, of which mainly complex formation with histone deacetylases (HDACs) leads to the repression of target genes. On the other hand, the role of posttranslational modifications in corepressor function is not well established. Here, we show that N-CoR is modified by Sumo-1. We found SUMO-E2-conjugating enzyme Ubc9 and SUMO-E3 ligase Pias1 as novel N-CoR interaction partners. The SANT1 domain of N-CoR was found to mediate this interaction. We show that K152, K1117, and K1330 of N-CoR can be conjugated to SUMO and that mutation of all sites is necessary to fully block SUMOylation in vitro. Because these lysine residues are located within repression domains I and III, respectively, we investigated a possible correlation between the functions of the repression domains and SUMOylation. Coexpression of Ubc9 protein resulted in enhanced N-CoR-dependent transcriptional repression. Studies using SUMOylation-deficient N-CoR RDI mutants suggest that SUMO modification contributes to repression by N-CoR. Mutation of K152 to R in RD1, for example, not only significantly reduced repression of a reporter gene, but also abolished the effect of Ubc9 on transcriptional repression.

Glucocorticoids inhibit activation-induced cell death (AICD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimer.

Glucocorticoids (GCs) play an important role in the regulation of peripheral T-cell survival. Their molecular mechanism of action and the question of whether they have the ability to inhibit apoptosis in vivo, however, are not fully elucidated. Signal transduction through the glucocorticoid receptor (GR) is complex and involves different pathways. Therefore, we used mice with T-cell-specific inactivation of the GR as well as mice with a function-selective mutation in the GR to determine the signaling mechanism. Evidence is presented for a functional role of direct binding of the GR to 2 negative glucocorticoid regulatory elements (nGREs) in the CD95 (APO-1/Fas) ligand (L) promoter. Binding of GRs to these nGREs reduces activation-induced CD95L expression in T cells. These in vitro results are fully supported by data obtained in vivo. Administration of GCs to mice leads to inhibition of activation-induced cell death (AICD). Thus, GC-mediated inhibition of CD95L expression of activated T cells might contribute to the anti-inflammatory function of steroid drugs.

Nuclear receptors: overview and classification.

The nuclear receptor superfamily comprises a large group of transcription factors that play a key regulatory role in development and homeostasis of multicellular organisms. A special feature of nuclear receptors is their ability to bind to condensed chromatin templates, which makes them important initiators of gene transcription. Moreover, the ability of nuclear receptors to sequentially recruit a variety of transcription factors and coregulators to target promoters and to orchestrate the whole process of gene transcription confirms their biological significance and stimulates intensive research and a high level of scientific interest in this field. In this review, we summarise current knowledge regarding the structure and function of nuclear receptors as principal regulators of gene expression. Emphasis is given to the molecular mechanisms of nuclear receptor-mediated transcriptional activation and repression including recent progress made in this area.