Transcript Document

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
Death
Death
Receptors
Receptors
Survival
Survival
Receptors
Receptors
Ask1
Ask1
Cyt-c
Cyt-c
Fas
Fas
DR5 FADD
Casp -8
Casp-8
PTEN
PI3K
Apaf-1
Apaf
Casp -9
Casp-9
IKK
BAD
BAX
Casp -3
Casp-3
Casp -6
Casp-6
DeathSubstrates
Death
Substrates
ICAD/DFF; PARP;
ICAD/DFF;
Gelsolvin , etc.
etc.
PARP; Gelsolvin
Reed JC,
Reed
JC,NDDR,
NDDR,2002
2002
p53
p53
kB
IIk
Bcl -2
Bcl-2
IAPs
IAPs
Casp -7
Casp-7
Akt
Bcl-X
Bcl
-XL
Bfl-1
PUMA
Nur77
Nur77
(TR3)
kB
NF-k
FKHD
FKHD
NOXA
kB
NF-k
Fas-L gene
Fas
gene
Receptor Mediated
(Extrinsic Pathway)
Mitochondrial –
Mediated (Intrinsic
Pathway)
FAS /
TRAIL
Fadd/
mort1
Mitochondria
CytochromeC
+
Apaf1
Caspase8
Caspase3
Caspase9
Receptor Mediated
(Extrinsic Pathway)
Mitochondrial –
Mediated (Intrinsic
Pathway)
FAS /
TRAIL
Fadd/
mort1
Mitochondria
FLIP
CytochromeC
+
Apaf1
Caspase8
Granzyme B
Caspase3
Caspase9
Receptor Mediated
(Extrinsic Pathway)
Mitochondrial –
Mediated (Intrinsic
Pathway)
FAS /
TRAIL
Fadd/
mort1
Mitochondria
CytochromeC
+
Apaf1
Caspase8
Granzyme B
Caspase3
Caspase9
XIAP
XIAP structure –function
BIR 1
?
BIR 2
BIR 3
RING
Casp –3/7
inhibition
Casp –9
inhibition
Ubiquitination
Receptor Mediated
(Extrinsic Pathway)
Mitochondrial –
Mediated (Intrinsic
Pathway)
FAS /
TRAIL
Fadd/
mort1
Bcl-2
Mitochondria
CytochromeC
+
Apaf1
Caspase8
Granzyme B
Caspase3
Caspase9
Receptor Mediated
(Extrinsic Pathway)
Mitochondrial –
Mediated (Intrinsic
Pathway)
FAS /
TRAIL
Fadd/
mort1
Bcl-2
FLIP
Mitochondria
CytochromeC
+
Apaf1
Caspase8
Granzyme B
Caspase3
Caspase9
XIAP
Bcl-2: apoptosis and cell
cycle
•
M
Mitochondria
Bcl-2
Cyto-c
G2
G1
S
Bax
Strategies to inhibit Bcl-2
Antisense
Oligonucleotides
Chemical
Bcl-2 Inhibitors
Bcl-2 Protein
Bcl-2 Protein
(with BH3 Peptide)