Professor Richard Christopherson
G08 - Biochemistry Building
Fludarabine induces proteins that regulate apoptosis in leukaemia cells
The purine analogues, cladribine and fludarabine, are effective as single agents in treating chronic lymphocytic leukaemia (CLL) and hairy cell leukaemia (HCL). The mechanisms of action of these anticancer drugs against CLL and HCL are being investigated using CD antibody (DotScan) microarrays and two-dimensional fluorescence differential gel electrophoresis (DIGE). We have found that both drugs induce significant changes in surface expression profiles on CLL cells, and in levels of several proteins involved in apoptosis.
Hsp90 inhibitors reduce oncogenic signalling proteins in leukaemia cells
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. The results obtained will provide insight on the mechanisms of action of these novel drugs.
Classification of leukaemias by cell surface profiling
DotScan antibody microarrays capture live leukaemia cells providing an extensive immunophenotype (surface expression profile or disease signature) for that leukaemia. This novel technology has been validated for classification of leukaemias by a clinical trial involving 796 patients. DotScan has also been used to identify significant changes induced in the immunophenotype of the human myeloid cell line, HL60, induced by all-trans retinoic acid (ATRA), Vitamin D and phorbol esters.
Surface profiling of colorectal cancers and detection of tumour-infiltrating lymphocytes (TILs)
DotScan has also been used to determine surface expression profiles of colorectal cancer (CRC) cells from surgically resected specimens. Using fluorescence multiplexing, expression profiles of CRC cells and tumour infiltrating lymphocytes (TILs) have been obtained from cancerous polyps. TILs may be very important in the future for cancer prognosis and for therapy that involves growing these TILs in vitro and infusing them back into the patient for immunotherapy.