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Overview of Targeted Therapy
MechanismsNovember 11, 2011
Targeted Therapies and Biological Therapies SIG
Targeted TherapiesProposed Mechanisms
GrowthFactor
RH Gunby et al. Oncogenic Fusion Tyrosine Kinases As Molecular Targets for Anti-Cancer Therapy. Anti-Cancer Agents in Medicinal Chemistry, 2007; 7:594-611. Images created by Kristine Abueg.
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NORMALGrowthFactor
Growth Factor
STOPsignal
Cell Signal Transduction• Extracellular Growth factor binds
with Surface Receptor• Surface receptors changes shape
(dimerization)• Phosphate group revealed• Tyrosine kinase sequence
activation (phosphorylation)• DNA activation• Controlled Cellular Division or
Activation
P
P
P P
GrowthFactor
RH Gunby et al. Oncogenic Fusion Tyrosine Kinases As Molecular Targets for Anti-Cancer Therapy. Anti-Cancer Agents in Medicinal Chemistry, 2007; 7:594-611. Images created by Kristine Abueg.
2
11
3
NORMALGrowthFactor
Growth Factor
STOPsignal
Cell Signal Transduction• Extracellular Growth factor binds
with Surface Receptor• Surface receptors changes shape
(dimerization)• Phosphate group revealed• Tyrosine kinase sequence
activation (phosphorylation)• DNA activation• Controlled Cellular Division or
Activation
P
P
P P
GrowthFactor
RH Gunby et al. Oncogenic Fusion Tyrosine Kinases As Molecular Targets for Anti-Cancer Therapy. Anti-Cancer Agents in Medicinal Chemistry, 2007; 7:594-611. Images created by Kristine Abueg.
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11
3
Watch Closely!GrowthFactor
Growth Factor
Controlled, Ordered Cellular Growth
Cell Signal Transduction• Extracellular Growth factor binds
with Surface Receptor• Surface receptors change shape
(dimerization)• Phosphate group revealed• Tyrosine kinase sequence
activation (phosphorylation)• DNA activation• Cellular Division or Activation
P
P
P P
GrowthFactor
211 3
When cells go awry!STOPsignal
GrowthFactor
GrowthFactor
Growth Factor
GrowthFactor
GrowthFactor
GrowthFactor
P
Excessive growth factors (overexpression)Excessive receptors (overexpression)Autodimerization
Autophosphorylation
Tyrosine Kinase self-activationLoss of inhibitory growth factors
GrowthFactor
211 3
Targeted Therapy Action
GrowthFactor
GrowthFactor
Growth Factor
GrowthFactor
GrowthFactor
GrowthFactor
P
Monoclonal Antibodies (MoAbs)inhibit cell surface and extracellular signaling
Tyrosine Kinase Inhibitors (TKI’s) inhibit intracellular protein kinase signalling
Beneficial Effects of Targeted Therapy
Cessation of signal transduction Cessation of cell duplication Cessation of metastatic properties (migration)
Apoptosis
ADCC: Antibody-Dependent Cell Cytotoxicity Direct cell kill Systemic immune interaction
Synergy with chemotherapy
Potential for targeted payload delivery – conjugated MoAb’s
