Deyati, Avisek: Knowledge Management Approaches for predicting Biomarker and Assessing its Impact on Clinical Trials. - Bonn, 2016. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
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author = {{Avisek Deyati}},
title = {Knowledge Management Approaches for predicting Biomarker and Assessing its Impact on Clinical Trials},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2016,
month = oct,

note = {The recent success of companion diagnostics along with the increasing regulatory pressure for better identification of the target population has created an unprecedented incentive for the drug discovery companies to invest into novel strategies for stratified biomarker discovery. Catching with this trend, trials with stratified biomarker in drug development have quadrupled in the last decade but represent a small part of all Interventional trials reflecting multiple co-developmental challenges of therapeutic compounds and companion diagnostics. To overcome the challenge, varied knowledge management and system biology approaches are adopted in the clinics to analyze/interpret an ever increasing collection of OMICS data. By semi-automatic screening of more than 150,000 trials, we filtered trials with stratified biomarker to analyse their therapeutic focus, major drivers and elucidated the impact of stratified biomarker programs on trial duration and completion. The analysis clearly shows that cancer is the major focus for trials with stratified biomarker. But targeted therapies in cancer require more accurate stratification of patient population. This can be augmented by a fresh approach of selecting a new class of biomolecules i.e. miRNA as candidate stratification biomarker. miRNA plays an important role in tumorgenesis in regulating expression of oncogenes and tumor suppressors; thus affecting cell proliferation, differentiation, apoptosis, invasion, angiogenesis. miRNAs are potential biomarkers in different cancer. However, the relationship between response of cancer patients towards targeted therapy and resulting modifications of the miRNA transcriptome in 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 created an unprecedented opportunity to decipher the role of miRNAs in early prediction of therapeutic efficacy in diseases. We present a novel SMARTmiR algorithm to predict the role of miRNA as therapeutic biomarker for an anti-EGFR monoclonal antibody i.e. cetuximab treatment in colorectal cancer. The application of an optimised and fully automated version of the algorithm has the potential to be used as clinical decision support tool. Moreover this research will also provide a comprehensive and valuable knowledge map demonstrating functional bimolecular interactions in colorectal cancer to scientific community. This research also detected seven miRNA i.e. hsa-miR-145, has-miR-27a, has- miR-155, hsa-miR-182, hsa-miR-15a, hsa-miR-96 and hsa-miR-106a as top stratified biomarker candidate for cetuximab therapy in CRC which were not reported previously. Finally a prospective plan on future scenario of biomarker research in cancer drug development has been drawn focusing to reduce the risk of most expensive phase III drug failures.},
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