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Lung Cancer. Placebo. Placebo. Placebo. Lymphoproliferative disorders. Placebo. Pooled data. Placebo. Pooled data. Placebo. OS= Overall survival PFS= progression free survival CIA = chemotherapy induced anemia. 2005. 2005. EPO improves survival If Hb<9.5. EPO does not impair

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  1. Lung Cancer Placebo Placebo

  2. Placebo Lymphoproliferative disorders Placebo

  3. Pooled data Placebo

  4. Pooled data Placebo

  5. OS= Overall survival PFS= progression free survival CIA = chemotherapy induced anemia

  6. 2005 2005 EPO improves survival If Hb<9.5 EPO does not impair PFS or Survival 2001 EPO may improve survival of Cancer patients 2001 EPO improves tumor control 2001 EPO improves ability to do daily activities 2001 EPO improves energy level 2001 EPO improves QOL in cancer pt. 2000 2000 EPO improves treatment control EPO relieves fatigue 1998 EPO reduces transfusion requirements 1998 EPO increases Hb levels

  7. HIF-1 =Hypoxia inducible factor 1 Hypoxia and tumors Nature Cancer Reviews 2:38, 2002

  8. Transcription Factors 1. HIF- 2. IGF 3. NF-kB Glycolysis 1. Gluc. Transporter (GLUT1,GLUT3) 2. Glycolysis enzymes Angiogenesis 1. Cox-2 2. NO synthase 3. VEGF 4. VEGF-R 5. Endothelin1,2 Oxygen Transport 1. Erythropoietin 2. Ceruloplasmin 3. Ferritin 4. Transferrin Energy requirements Blood supply Effects of Hypoxia Reduced Oxygen HIF- ARNT Hypoxia Response Elements HIF= Hypoxia inducible factor Nature Cancer Reviews 2:38, 2002 13

  9. Why should tumors produce ERYTHROPOIETIN? Would EPO increase their oxygenation ? Would EPO support tumor angiogenesis? Could Erythropoietin be a growth factor for cancer cells?

  10. 2000 Tumors produce EPO

  11. In vitro studies

  12. 2001

  13. 2001

  14. Cancer cells express EPO-R 2001 2000 Tumors produce EPO

  15. 2002

  16. 2002

  17. 2002

  18. AKT Does it make any sense? What are the mechanisms of cancer cell stimulation?

  19. EPO promotes survival of cancer cells 2002 2002 EPO is a growth factor for cancer cells 2000 Tumors produce EPO Cancer cells express EPO-R 2001

  20. 2002

  21. 2002

  22. 2002

  23. 2002 So, we have to inhibit EPO in cancer patients, not to administer it !?

  24. 2003

  25. 2003

  26. 2003

  27. 2003

  28. 2003

  29. EPO promotes survival of cancer cells 2002 2002 EPO is a growth factor for cancer cells 2003 2003 EPO promotes angiogenesis of cancer. EPO protects cancer cells from apoptosis 2000 Tumors produce EPO Cancer cells express EPO-R 2001

  30. Why should tumors induce ERYTHROPOIETIN production? To increase their oxygenation ? To support angiogenesis? Could Erythropoietin be a growth factor for cancer cells?

  31. Blood vessels may still grow and promote tumor growth even if the tumor itself has no EPO-R. Tumor cell EPO receptor

  32. Clinical studies

  33. 2003

  34. 2003

  35. 2003 Locoregional progression free survival

  36. Locoregional progression free survival No residual disease 2003 Definitive radiation Residual disease

  37. 2003

  38. 2003 EPO compromised survival In head and neck cancer pt. 2000 Tumors produce EPO Cancer cells express EPO-R 2001 EPO promotes survival of cancer cells 2002 2002 EPO is a growth factor for cancer cells 2003 EPO promotes cancer angiogenesis 2003 EPO protects cancer cells from apoptosis

  39. 2003 BEST trial

  40. 2003 939 patients with metastatic breast cancer

  41. 2003 Why these findings are called “unexpected”?

  42. 2003

  43. 2003 EPO compromised survival In head and neck cancer pt. 2003 EPO compromised survival In breast cancer (>12Hb).BEST 2003 EPO accelerated breast cancer Progression. BEST 2000 Tumors produce EPO Cancer cells express EPO-R 2001 EPO promotes survival of cancer cells 2002 EPO is a growth factor for cancer cells 2002 EPO promotes cancer angiogenesis 2003 2003 EPO protects cancer cells from apoptosis

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