Pharmacogenomics is a rapidly evolving discipline with vast potential for improving clinical care during the early part of the 21st century via more selective targeting of, in particular, novel therapeutic agents. The principle of pharmacogenomics is the direct targeting of treatment to a specific molecular alteration manifested within a disease state using specific clinical diagnostic tests. In oncology, pharmacogenomics started with the development of targeted therapy against oestrogen receptor (ER) positive breast cancers in the 1960s.
The subsequent development of Herceptin (targeting the HER2 oncogene in breast cancer) and Glivec (targeting BCR-Abl translocation in leukaemia) confirmed the close relationship between target expression and clinical therapeutic response. Both these successful treatments depend upon appropriate pharmacodiagnostics for identification of patients whose tumours express their targets. This proposal aims to pursue the development of pharmacodiagnostic assays based upon activation of specific proteins involved in hormone resistance in both breast and prostate cancer (in particular the two steroid receptors, ER and androgen receptor (AR) and their co-activators, AIB1/SRC1 as well as the AKT/mTOR pathway) by developing and validating novel diagnostic assays using phosphospecific antibodies.
These assays will be used to rapidly screen tissue banks isolated within the context of current and future clinical trials to identify novel markers which act as pharmacodiagnostics for conventional and/or novel pharmacogenomic agents. Using materials from clinical trials, our concept is to identify those genes or gene products, which predict patient outcome in response to specific therapeutic interventions, and thus function as pharmacodiagnostics. In addition we will establish a paradigm for developing of high quality and robust reagents to evaluate activated proteins within human tissues.
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