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What can we learn from the identification of specific molecular abnormalities in malignant disease? •Insights into normal cell biology •Targets for diagnosis and follow-up •Targets for rational drug design Conventional cytotoxic drugs mainly act by causing DNA damage and cell death Studying the biology of cancer cells may provide new targets for drug development Signal transduction modules Molecular links between changes in cell environment and cellular responses Signalling pathways control cell functions Replicate QuickTime™ and a Sorenson Video decompressor are needed to see this picture. Live/Die QuickTime™ and a Sorenson Video decompressor are needed to see this picture. Move QuickTime™ and a Sorenson Video decompressor are needed to see this picture. Signal transduction modules Molecular links between changes in cell environment and cellular responses e.g. •Erythropoietin and prevention of apoptosis in erythroid progenitors •G-CSF and proliferation in myeloid progenitors The hallmarks of cancer Many of these features may result from abnormalities in signalling components (Hanahan & Weinberg (2000) Cell 100, 57) Ligand binding dimerizes receptor tyrosine kinases resulting in their activation Monomeric receptor Dimeric receptor P P No ligand P P Ligand present A number of signalling modules link growth factor receptor binding to changes in cell function Ras MAPK P P P P STAT Activation of gene transcription PI3-kinase PKB The Ras protein acts as a molecular switch in response to changes in the external environment of the cell Growth factor OFF Ras.GDP GTPase activating protein e.g. NF-1 Proliferation Exchange factor e.g. SOS Ras.GTP ON Survival Movement RAS SH3 SH2 GRB2 GDP SOS GTP SOS Recruitment of a Grb2-SOS complex to an activated receptor tyrosine kinase mediates Ras activation SH3 SH2 GRB2 P P P P Examples of signalling pathway abnormalities in haematological malignancy Aberrant tyrosine kinase activity Bcr-Abl CML Increased Ras activity point mutation loss of NF1 AML QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. The constitutive activity of the Bcr-Abl tyrosine kinase bypasses the requirement for growth factors Bcr-Abl Ras MAPK PI3-kinase STAT PKB Activation of gene transcription Increased proliferation/survival Examples of signalling pathway abnormalities in haematological malignancy Aberrant tyrosine kinase activity Bcr-Abl CML Increased Ras activity point mutation loss of NF1 AML AML AML Normal Ras proteins are frequently activated by point mutation in human cancers OFF Ras.GDP Exchange factor e.g. SOS NF-1 MUTANT Ras.GTP ON Proliferation Survival Carcinoma •pancreas •colon •thyroid •AML •Myeloma Invasion Loss of the NF-1 protein results in excessive Ras activation OFF Ras.GDP Neurofibromatosis •Myeloid leukaemias Ras.GTP ON Proliferation Survival Invasion Molecular targets in leukaemia therapy Signal transduction pathways Dysregulated kinases eg Bcr-Abl Mutant Ras proteins Apoptosis pathways Bcl-2, NF-kappaB, p53 Differentiation pathways Retinoic acid receptor Histone deacetylases Imatinib mesylate inhibits the activity of Bcr-Abl by competing with ATP and is effective in the treatment of CML Addition of a farnesyl (C15) moiety is required for Ras proteins to be active Plasma membrane Ras Farnesyl transferase Ras active -CAAX Cytoplasm inactive F -C-OMe Targeting Ras proteins by inhibiting membrane localisation Plasma membrane Farnesyl transferase Ras FT Inhibitors -CAAX Cytoplasm inactive The transcription factor NF-kB induces transcription of pro-survival genes and is constitutively activated in a variety of tumours NIK NEMO IKK1 IkB IKK2 P IkB NF-kB Degradation by proteasome NF-kB Increased transcription eg Bcl-2 Inhibitors of proteasomal activity prevent NF-kB activation by blocking IkB degradation Proteasome inhibitor Eg PS-341 NIK NEMO IKK1 IkB IKK2 P IKK inhibitors IkB NF-kB Reduced transcription What can we learn from the identification of specific molecular abnormalities in malignant disease? •Insights into normal cell biology •Targets for diagnosis and follow-up •Targets for rational drug design