1. Novel agents targeting the apoptosis pathway Aaron D. Schimmer MD, PhD, FRCPC Princess Margaret Hospital Toronto, Canada

2. Cancer is an Elephant Cancer is a defect In apoptosis

3. Therapy Biology

4. Apoptosis

5. Ask1 FADD Apaf - - 1 1 Casp-9 -9 -3 -3 -7 -7 -6 -6 BAD Casp-8 Akt Cyt- c p53 Death Substrates ICAD/DFF; PARP; Gelsolvin, etc. IAPs BAX Bcl-2 -X L Bfl-1 PUMA NOXA NF- k B I k B IKK PI3K Fas - - L gene FKHD Nur77 (TR3) Fas DR5 NF- k B Flip PTEN Death Receptors Survival Receptors Reed JC, NDDR, 2002 Ask1 FADD Apaf - - 1 1 Casp-9 -9 -3 -3 -7 -7 -6 -6 BAD Casp-8 Akt Cyt- c p53 Death Substrates ICAD/DFF; PARP; Gelsolvin, etc. IAPs BAX Bcl-2 -X L Bfl-1 PUMA NOXA NF-  B I  B IKK PI3K Fas - - L gene FKHD Nur77 (TR3) Fas DR5 NF-  B Flip PTEN Death Receptors Survival Receptors Reed JC, NDDR, 2002

7. Mitochondria Cytochrome - - C C Caspase- 9 - 3 - 8 Fadd/ mort1 FAS / TRAIL + Apaf- 1 Mitochondrial– Mediated (Intrinsic Pathway) Receptor Mediated (Extrinsic Pathway )

8. Mitochondria Cytochrome - - C C Caspase- 9 - 3 - 8 Fadd/ mort1 FAS / TRAIL Granzyme B + Apaf- 1 Mitochondrial– Mediated (Intrinsic Pathway) Receptor Mediated (Extrinsic Pathway ) FLIP

9. Mitochondria Cytochrome - - C C Caspase- 9 - 3 - 8 Fadd/ mort1 FAS / TRAIL Granzyme B + Apaf- 1 Mitochondrial– Mediated (Intrinsic Pathway) Receptor Mediated (Extrinsic Pathway ) XIAP

10. ? Casp –3/7 inhibition Ubiquitination BIR 1 BIR 1 RING BIR 2 BIR 2 BIR 3 BIR 3 Casp –9 inhibition XIAP structure –function

11. Mitochondria Cytochrome - - C C Caspase- 9 - 3 - 8 Fadd/ mort1 FAS / TRAIL Granzyme B + Apaf- 1 Mitochondrial– Mediated (Intrinsic Pathway) Receptor Mediated (Extrinsic Pathway ) Bcl-2

12. Mitochondria Cytochrome - - C C Caspase- 9 - 3 - 8 Fadd/ mort1 FAS / TRAIL Granzyme B + Apaf- 1 Mitochondrial– Mediated (Intrinsic Pathway) Receptor Mediated (Extrinsic Pathway ) XIAP FLIP Bcl-2

13. Bcl-2: apoptosis and cell cycle Mitochondria Cyto-c Bcl-2 Bcl-2 Bax M S G1G1 G2G2

14. Strategies to inhibit Bcl-2 Antisense Oligonucleotides Chemical Bcl-2 Inhibitors

15. Bcl-2 Protein

16. (with BH3 Peptide)