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

Live/Die

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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

(Hanahan & Weinberg (2000) Cell 100, 57)

The hallmarks of cancer

Many of these features may result from abnormalities in signalling components

Ligand binding dimerizes receptor tyrosine kinases resulting in their activation

No ligand

Monomeric receptor

Ligand present

Dimeric receptor

P

PP

P

A number of signalling modules link growth factor receptor binding to changes in cell function

P

PP

P

Activation of gene transcription

Ras PI3-kinase

STATMAPK PKB

Ras.GDP

Ras.GTPON

OFF

GTPase activating proteine.g. NF-1

Proliferation Survival Movement

Exchange factore.g. SOS

The Ras protein acts as a molecular switch in response to changes in the external environment of the cell

Growth factor

Recruitment of a Grb2-SOS complex to an activated receptor tyrosine kinase mediates

Ras activation

P

PP

P

SH3 SH2

GRB2SO

S

SH3 SH2

GRB2SO

SRAS

GDPGTP

Examples of signalling pathway abnormalities in haematological

malignancy

Aberrant tyrosine kinase Bcr-Abl CMLactivity

Increased Ras activity point mutation AMLloss of NF1

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The constitutive activity of the Bcr-Abl tyrosine kinase bypasses the requirement for growth factors

Bcr-Abl

Activation of gene transcriptionIncreased proliferation/survival

RasPI3-kinase

STATMAPK PKB

Examples of signalling pathway abnormalities in haematological malignancy

Aberrant tyrosine kinase Bcr-Abl CMLactivity

Increased Ras activity point mutation AMLloss of NF1

AML AML

Normal

Ras proteins are frequently activated by point mutation in human cancers

Ras.GDP

MUTANTRas.GTP

ON

OFF

NF-1

Proliferation Survival Invasion

Exchange factore.g. SOS

Carcinoma•pancreas•colon•thyroid

•AML•Myeloma

Loss of the NF-1 protein results in excessive Ras activation

Ras.GDP

Ras.GTPON

OFF

Proliferation Survival Invasion

Neurofibromatosis•Myeloid leukaemias

Molecular targets in leukaemia therapy

Signal transduction pathwaysDysregulated kinases eg Bcr-AblMutant Ras proteins

Apoptosis pathwaysBcl-2, NF-kappaB, p53

Differentiation pathwaysRetinoic acid receptorHistone 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

Ras

inactive

-CAAX

Ras -C-OMe

F

active

Cytoplasm

Plasma membrane

Farnesyltransferase

Targeting Ras proteins by inhibiting membrane localisation

Ras

inactive

-CAAXCytoplasm

Plasma membrane

Farnesyltransferase

FT Inhibitors

The transcription factor NF-B induces transcription of pro-survival genes and is constitutively activated

in a variety of tumours

IkBNF-kB

IKK1 IKK2NEMO

NF-kB

Increased transcriptioneg Bcl-2

NIK

IkB Degradation by proteasome

P

Inhibitors of proteasomal activity prevent NF-kB activation by blocking IkB degradation

IkBNF-kB

IKK1 IKK2NEMO

NIK

IkB

P

Proteasome inhibitorEg PS-341

Reduced transcriptionIKK inhibitors

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