1. Overview of Targeted Therapy Mechanisms November 11, 2011 Targeted Therapies and Biological Therapies SIG

2. Targeted Therapies Proposed Mechanisms

3. Growth Factor 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 1 1 3 NORMAL Growth Factor STOP signal 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

4. Growth Factor 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 1 1 3 NORMAL Growth Factor STOP signal 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

5. Growth Factor 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 1 1 3 Watch Closely! 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

6. Growth Factor 2 1 1 3 When cells go awry! STOP signal Growth Factor P Excessive growth factors (overexpression) Excessive receptors (overexpression) Autodimerization Autophosphorylation Tyrosine Kinase self-activation Loss of inhibitory growth factors

7. 2 1 1 3 Targeted Therapy Action Growth Factor P Monoclonal Antibodies (MoAbs) inhibit cell surface and extracellular signaling Tyrosine Kinase Inhibitors (TKI’s) inhibit intracellular protein kinase signalling

8. Beneficial Effects of Targeted Therapy Cessation of signal transduction Cessation of signal transduction Cessation of cell duplication Cessation of cell duplication Cessation of metastatic properties (migration) Cessation of metastatic properties (migration) Apoptosis Apoptosis ADCC: Antibody-Dependent Cell Cytotoxicity ADCC: Antibody-Dependent Cell Cytotoxicity Direct cell kill Direct cell kill Systemic immune interaction Systemic immune interaction Synergy with chemotherapy Synergy with chemotherapy Potential for targeted payload delivery – conjugated MoAb’s Potential for targeted payload delivery – conjugated MoAb’s