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

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Presentation transcript:

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

Cancer is an Elephant Cancer is a defect In apoptosis

Therapy Biology

Apoptosis

Ask1 FADD Apaf Casp 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 Casp 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

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

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

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

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

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

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

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

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

Bcl-2 Protein

(with BH3 Peptide)