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1. Introduction
2. Historical perspective on CML
3. Clinical description of CML
4. History of CML
5. Chronic myeloid leukemia (CML)
6. Phases of CML
7. Stable phase of CML
8. Advanced stages of CML
9. Molecular pathogenesis of CML
10. Philadelphia chromosome
11. Molecular pathogenesis of CML - translocation
12. BCR-ABL as a therapeutic target
13. Blocking ATP binding as therapy for CML
14. Imatinib
15. Summary of preclinical data
16. Phase I clinical trials of Imatinib
17. Response to Imatinib 500 Mg
18. Phase II studies
19. Summary of phase II data
20. Relapse rate
21. Phase III studies - Interferon + Ara-C vs. Imatinib
22. Enrollment
23. Summary of 18 months data
24. Progression-free survival
25. Summary of CML clinical trials
26. Why do some patients relapse?
27. BCR-ABL substrates
28. CRKL protein
29. Reactivation of BCR-ABL kinase at relapse
30. The reason for the relapse in some patients
31. ABL kinase domain mutations
32. Inhibition of cell proliferation by Imatinib
33. Contact sites of ABL and Imatinib
34. P loop mutants
35. Structure of ABL kinase domain
36. Imatinib vs. AMN107
37. Inhibition of cell proliferation by AMN107
38. SRC/ABL inhibitors for Imatinib-resistance
39. Inhibition of cell proliferation by SRC/ABL inhibitor
40. Clinical trials of novel ABL inhibitors
41. Imatinib and GIST
42. Gastrointestinal stromal tumors (GIST)
43. Gist patients response to Imatinib
44. Pet scan in GIST
45. Extending the Imatinib paradigm
46. Expression versus response
47. Imatinib response in advanced malignancies
48. Expression correlates with response
49. Is expression sufficient to predict response?
50. Activation versus response
51. Response to Imatinib in GIST patients
52. Gefitinib and Erlotinib
53. Expression of target doesn't guarantee response
54. Meaning of low response rate
55. Response to Imatinib in GIST patients not zero
56. PDGFR activating mutations in GIST
57. Clinical trials with Imatinib - conclusions
58. BCR-ABL as an ideal target
59. KIT as an ideal target in GIST
60. Clinical trials with Imatinib - old conclusions
61. Responses by phase of disease
62. Applying Imatinib success to other malignancies
63. The 21 century - future plans
64. Acknowledgements
65. Patients picture

Topics Covered

• Clinical description of chronic myeloid leukemia (CML)
• Molecular pathogenesis of CML
• The BCR-ABL tyrosine kinase as a therapeutic target
• Preclinical and clinical development of the ABL tyrosine kinase inhibitor, imatinib
• Mechanisms of resistance to imatinib
• Development of novel ABL tyrosine kinase inhibitors for imatinib-resistant CML
• Imatinib and gastrointestinal stromal tumor
• Extending the imatinib paradigm
• Lessons learned from the clinical trials of imatinib

Links

Series:

• Signal Transduction via Protein Tyrosine Kinase Receptors
• Small Molecule Drug Discovery

Categories:

• Cancer
• Pharmaceutical Sciences

Therapeutic Areas:

• Oncology

Talk Citation

Publication History

• Published on October 1, 2007
• Archived on May 31, 2018

Financial Disclosures

• Prof. Brian Druker has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.