“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 ?

Individuals respond differently to the same chemotherapy Development of resistance to chemo Incomplete understanding of crucial survival pathways

Proliferate Migrate Differentiate Die Proliferate Migrate Differentiate Die Things Cells Can Do Causes Cancer Prevents Cancer

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

Eadweard Muybridge 1878

Cleavage of substrates APOPTOSIS zymogens casp-7 casp-3 EXECUTION INITIATION (Commitment) Casp-8 Death receptor EXTRINSIC PATHWAY death ligand delivered to death receptor adaptor Bax INTRINSIC PATHWAY mitochondrial assembly of pro-apoptotic factors casp-9 Apaf-1 cyto C STRESS Bcl2 mitochondrion XIAP REPRIEVAL

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 FLIP L FADD

FLIPCasp-8 Cleavage of substrates APOPTOSIS zymogens casp-7 casp-3 Casp-8 Death receptor EXTRINSIC PATHWAY death ligand delivered to death receptor adaptor Casp-8 adaptor RIPK1 RIPK3 HDAC7 Cleavage of substrates SURVIVAL X X No cleavage of substrates Metabolic overload NECROSIS X X No cleavage of substrates PROLIFERATION XIAP REPRIEVAL

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 Oberst Doug Green Alex Trembley J-B Denault Sabine Leverrier Craig Walsh Christian Zmasek NIANINDSNCINHLBINIBIB