Transcript CURE PPT - Salvesen Lab

“Cutting Edge”
Cancer Research
Guy Salvesen, PhD
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
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….
Good and bad news
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
Things Cells Can Do
Causes
Cancer
Proliferate
Migrate
Differentiate
Die
Prevents
Cancer
APOPTOSIS
APOPTOSIS
Cancer
Autoimmune Disease
Restenosis
AIDS
Ischemic Disease
Neurodegeneration
APOPTOSIS
Cancer
Autoimmune Disease
AIDS
Ischemic Disease
Neurodegeneration
apoptosis
apoptosis
Imre Kovacs
apoptosis
Imre Kovacs
Carle-Vernet 1805-10
Eadweard Muybridge 1878
Eadweard Muybridge 1878
Eadweard Muybridge 1878
EXTRINSIC PATHWAY
death ligand
delivered to
death receptor
Death receptor
STRESS
adaptor
INITIATION
(Commitment)
Casp-8
Bcl2
Bax
mitochondrion
zymogens
casp-9
XIAP
EXECUTION
Apaf-1
cyto C
casp-3
casp-7
INTRINSIC PATHWAY
mitochondrial assembly
of pro-apoptotic factors
Cleavage of substrates
APOPTOSIS
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
FADD
FLIPL
EXTRINSIC PATHWAY
death ligand
delivered to
death receptor
Death receptor
adaptor
adaptor
Casp-8
Casp-8
X
X
Casp-8
FLIP
X
zymogens
XIAP
casp-3
X
RIPK1
RIPK3
HDAC7
No cleavage of substrates
casp-7
Cleavage of substrates
Metabolic overload
SURVIVAL
NECROSIS
No cleavage
of substrates
Cleavage
of substrates
PROLIFERATION
APOPTOSIS
Assuming this
hypothesis is correct –
design a therapy to kill
cancer cells by
targeting caspase-8
The origin of adaptive immunity
Laird D J et al. PNAS 2000
©2000 by The National Academy of Sciences
Earliest caspase-8 ancestor
Thanks for the help
Scott Snipas
Stefan Riedl
Andrew Oberst
Doug Green
Alex Trembley
J-B Denault
Sabine Leverrier
Craig Walsh
Christian Zmasek
NCI NIBIB
NHLBI
NIA NINDS