Hsp90 inhibitors reduce oncogenic signalling proteins in leukaemia cells.
Many cancers grow rapidly and without control due to stimulation of signalling pathways that can be blocked with Hsp90 inhibitors.
Pathways for intracellular signaling are up-regulated in many cancers. Heat shock protein 90 (Hsp90) inhibitors such as 17-AAG are undergoing clinical trials for treatment of a variety of cancers. Hsp90 is a molecular chaperone that catalyzes the conformational maturation of a number of oncogenic signalling proteins with the hydrolysis of ATP. Inhibitors such as 17-AAG prevent the binding of ATP to Hsp90, resulting in the release and degradation of signalling proteins required for the growth of cancer. We have found that several Hsp90 inhibitors induce significant changes in the surface expression profiles and cellular proteomes of CLL and other leukaemias. CD antibody microarrays and complete proteomic analysis of sub-cellular fractions using two-dimensional fluorescence difference gel electrophoresis (DIGE) will be used to identify proteins whose levels change in leukaemia cells treated with Hsp90 inhibitors. The results obtained will provide insight on the mechanisms of action of these novel drugs.
Projects will involve initial experiments with leukaemia, colorectal cancer and melanoma cell lines. With the analytical procedures established further experiments will be conducted with primary cancer samples from patients to see if the results obtained translate from model cell lines to actual cancers.
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The opportunity ID for this research opportunity is: 131