1. “Cutting Edge” Cancer Research Guy Salvesen, PhD

2. 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

3. Good and bad news

4. WHY DON’T WE HAVE CANCER UNDER CONTROL YET ?

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

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

8. APOPTOSIS

9. Cancer Autoimmune Disease Restenosis AIDS Ischemic Disease Neurodegeneration APOPTOSIS

10. Cancer Autoimmune Disease AIDS Ischemic Disease Neurodegeneration APOPTOSIS

11. apoptosis Imre Kovacs

12. apoptosis Imre Kovacs

13. Carle-Vernet 1805-10

14. Eadweard Muybridge 1878

18. 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

19. Caspase animations Kelly Boatright

20. Assembly of the DISC Fas casp8 FADD

21. The Space Between Proliferation and Death

22. Non-apoptotic roles for caspase-8

24. RIPK3 deficience rescues the developmental defect – but cannot rescue the apoptosis defect Treated with Fas Ligand (activates caspase-8)

25. 4 weeks 15weeks

26. Artificial dimerization of caspase-8 and FLIP Cristina Pop

27. FLIP moderately alters caspase-8 specificity

28. Assembly of the DISC Fas casp8 FLIP L FADD

29. 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

30. Assuming this hypothesis is correct – design a therapy to kill cancer cells by targeting caspase-8

31. Laird D J et al. PNAS 2000 ©2000 by The National Academy of Sciences Earliest caspase-8 ancestor The origin of adaptive immunity

32. Thanks for the help Scott Snipas Stefan Riedl Andrew Oberst Doug Green Alex Trembley J-B Denault Sabine Leverrier Craig Walsh Christian Zmasek NIANINDSNCINHLBINIBIB