“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

apoptosis

Imre Kovacs

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