Molecular Networks and the Mechanism of Action of Anticancer Agents
|Starts:||13:00 5 Feb 2014|
|Ends:||14:00 5 Feb 2014|
|What is it:||Seminar|
|Organiser:||Faculty of Life Sciences|
|Who is it for:||University staff|
This seminar is part of the Special Seminar Series
Biologically active chemical compounds produce complex molecular responses already at the cellular levels. The majority of compounds bind to several proteins: proteins of the cognate target class, those for which the compound was designed, but often also proteins bearing completely different folds. These proteins affect different pathways and cellular processes. While we usually monitor the net outcome of all these interactions in terms of selected biological readouts we are mostly oblivious of the intricacies that occur at the molecular level. We have investigated the mechanism of action of several compounds in clinical use against cancer, mostly of hematological origin. We used a number of approaches, ideally in parallel: 1) chemical proteomics (affinity purifications using immobilized drug matrices followed by mass spectrometry), 2) chemical genetics (random mutagenesis of genome of near-haploid CML cells), 3) functional proteomics (affinity purification / mass spectrometry), 4) transcriptional profiling , 5) phosphoproteomics (where appropriate), 6) computational network analysis and modeling (protein-protein, drug-protein, protein-disease a.s.o.), and 7) validation by focused gene inactivation (RNAi and genome editing). We try to obtain a detailed picture of the actual molecular events and requirements of the drugs under investigation. Using this integrated approach we have identified: 1) new targets for known drugs, 2) previously unknown mechanisms of drug resistance, 3) “effector” genes for the compounds (genes required for the drug to exert its action), 4) mechanisms of synergy between compounds and in a few cases 5) new medical use of existing drugs. We hope that systematic adoption of this more rigorous and “systems-level” characterization of chemical entities will help understanding the biology of drug action better and allow the development of improved drugs. We also believe it should help the community in rationalizing patient stratification, thus increasing the efficacy of clinical trials and reduce unwanted side effects, but also contribute to the employment of mechanism-based combination therapy with existing drugs.
Bürckstümmer, T. et al (2013). A reversible gene trap collection empowers haploid genetics in human cells. Nat Methods 10, 965-971.
Host:Douglas Kell, MIB
Role: CEO & Scientific Director
Organisation: Research Centrer for Molecular Medicine of the Austrian Academy of Sciences
Travel and Contact Information
MIB Lecture Theatre
Manchester Interdisciplinary Biocentre - John Garside Building