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“Cutting Edge”Cancer Research
Guy Salvesen, PhD
Overall cancer incidence rates decreased by approximately 1% per year; the decrease was statistically significant (P < .05) in women, but not in men, because of a recent increase in prostate cancer incidence……
The decrease in cancer incidence and mortality reflects progress in cancer prevention, early detection, and treatment. However, major challenges remain, including increasing incidence rates and continued low survival for some cancers….
Annual Report to the Nation on the Status of Cancer,1975–2007, Featuring Tumors of the
Brain and Other Nervous System
J Natl Cancer Inst 2011;103:1–23
Good and bad news
WHY DON’T
WE HAVE
CANCER UNDER
CONTROL YET ?
WHY DON’T
WE HAVE
CANCER UNDER
CONTROL YET ?
Individuals respond differently to the same chemotherapy
Development of resistance to chemo
Incomplete understanding of crucial survival pathways
Individuals respond differently to the same chemotherapy
Development of resistance to chemo
Incomplete understanding of crucial survival pathways
ProliferateMigrate
DifferentiateDie
ProliferateMigrate
DifferentiateDie
Things Cells Can Do
Causes Cancer
Prevents Cancer
APOPTOSIS
CancerAutoimmune DiseaseRestenosis
AIDSAIDSIschemic DiseaseIschemic Disease
NeurodegenerationNeurodegeneration
APOPTOSIS
CancerCancerAutoimmune DiseaseAutoimmune Disease
AIDSIschemic Disease
Neurodegeneration
APOPTOSIS
apoptosis
Imre Kovacs
Carle-Vernet 1805-10
Eadweard Muybridge 1878
Eadweard Muybridge 1878
Eadweard Muybridge 1878
Cleavage of substratesAPOPTOSIS
zymogens
casp-7casp-3EXECUTION
INITIATION(Commitment)
Casp-8
Death receptor
EXTRINSIC PATHWAY death ligand delivered to death receptor
adaptor
Bax
INTRINSIC PATHWAYmitochondrial assembly of pro-apoptotic factors
casp-9
Apaf-1cyto C
STRESS
Bcl2
mitochondrionmitochondrion
XIAP
REPR
IEVA
L
Caspase animations
Kelly Boatright
Assembly of the DISC
Fas
casp8
FADD
The Space Between Proliferation and Death
Non-apoptotic roles for caspase-8
RIPK3 deficience rescues the developmental defect – but cannot rescue the apoptosis defect
Treated with Fas Ligand (activates
caspase-8)
4 weeks 15weeks
Artificial dimerization of caspase-8 and FLIP
Cristina Pop
FLIP moderately alters caspase-8 specificity
Assembly of the DISC
Fas
casp8
FLIPL
FADD
FLIPCasp-8
Cleavage of substratesAPOPTOSIS
zymogens
casp-7casp-3
Casp-8
Death receptor
EXTRINSIC PATHWAY death ligand delivered to death receptor
adaptor
Casp-8
adaptor
RIPK1
RIPK3
HDAC7
Cleavage of substratesSURVIVAL
XX
No cleavage of substratesMetabolic overload
NECROSIS
XX
No cleavage of substratesPROLIFERATION
XIAP
REPR
IEVA
L
Assuming this hypothesis is correct – design a therapy to kill
cancer cells by targeting caspase-8
Laird D J et al. PNAS 2000
©2000 by The National Academy of Sciences
Earliest caspase-8 ancestor
The origin of adaptive immunity
Thanks for the help
Scott Snipas
Stefan Riedl
Andrew OberstDoug Green
Alex TrembleyJ-B Denault
Sabine LeverrierCraig Walsh
Christian Zmasek
NIA NINDSNCI NHLBINIBIB
