Retroviruses can cause cancer by picking up mutated versions of normal cellular genes

1. Retroviruses can cause cancer by picking up mutated versions of normal cellular genes Alberts et al. Fig. 24-23

2. Many viral oncogenes are kinases, including RTKs Alberts et al.

3. Different families of RTKs recognize a diverse set of different ligands Alberts et al. Fig. 15-47

4. Ligand binding activates RTKs by dimerization Lodish et al. Fig. 20-21

5. RTK signaling ultimately leads to activation of a transcription factor Gilbert Fig. 6.14

6. Most ligands that induce receptor dimerization act as dimers Alberts et al. Fig. 15-48

7. EGF and TGF-alpha induce receptor dimerization by an unusual mechanism Garrett et al., Ogiso et al., Cell 2002, 110: 763, 775

8. Neu = HER2 was first found in a Neuroblastoma cell line “Neuroblastoma is one of the most common solid tumours of early childhood usually found in babies or young children. The disease originates in the adrenal medulla or other sites of sympathetic nervous tissue. The most common site is the abdomen (near the adrenal gland) . Most patients have widespread disease at diagnosis.” http://www.cancerindex.org

9. "I prefer the clustering model- a series of receptors on the membrane .... all have to bind with growth factor more or less simultaneously.... Only after they are clustered are they able to send along the signal... The insertion of a glutamic acid into the transmembrane domain could trick the neu protein into believing it was surrounded by other neu receptors even when it stood alone" Cori Bargmann today

10. Activating mutations in RTKs take several forms but all lead to ligand-independent dimerization and thus activation Lodish et al. Fig. 24-16

11. A chimeric oncogenic version of the trk RTK was isolated from a human colon carcinoma Tropomyosin dimerization dimerizes the receptor even in the absence of ligand Lodish et al. Fig. 24-16

12. Gene amplification is also a common mechanism of inappropriate gene activation in human tumors Double minute chromosomes Tandem duplications Alberts et al. Fig. 24-20

13. An example of an inhibitor (in red and green) designed to block the active site of the insulin receptor tyrosine kinase (in gray)

14. An example of an inhibitor (in red and green) designed to block the active site of the insulin receptor tyrosine kinase (in gray) Iressa, an EGFR inhibitor

15. Gefitinib (Iressa), an EGFR inhibitor was approved after Phase II trials for “third line” treatment of non-small cell lung cancer Curr Treat Options Oncol. 2005 6:75-81 www.iressa-us.com

16. Gefitinib (Iressa), an EGFR inhibitor was approved after Phase II trials for “third line” treatment of non-small cell lung cancer But Phase III clinical trial data From December 2004 raise serious questions about whether it prolongs life. It may work in just fraction of cases Curr Treat Options Oncol. 2005 6:75-81 www.iressa-us.com

17. Data suggest that Gefitinib (Iressa) may benefit a subset of patients Including “never-smokers” and Patients of Asian descent Curr Treat Options Oncol. 2007 Feb;8(1):28-37

18. It has been partially replaced by Erlotinib (Tarceva), another EGFR inhibitor approved for “second line” treatment of non-small cell lung cancer Median Survival: 6.7 months vs. 4.7 months in placebo control www.tarceva.com

19. Four second generation EGFR inhibitors are now entering clinical trials EKB-569, HKI-272, CI-1033, and ZD6474 • Covalently bind EGFR • Target multiple kinases including HER2 and VEGFR The Oncologist, Vol. 12, No. 3, 325-330, March 2007

20. Genentech.com

21. Herceptin-- The corporate view

22. Genentech.com

23. Antibodies have been crafted by natural selection to allow recognition of diverse antigens from bacterial, viral, and parasitic invaders Alberts et al. Fig. 23-31

24. The 3-dimensional structure of an antibody Alberts et al. Fig. 23-34

25. The antibody-antigen recognition event is exquisitely specific Yellow and blue= heavy and light chains Green=antigen Red= amino acids in contact Alberts et al. Fig. 23-35

26. Data from Phase III clinical trials of Herceptin Genentech.com

27. Data from Phase III clinical trials of Herceptin Genentech.com

28. Herceptin is now approved for treatment of Metastatic breast cancer

29. However, even more exciting is recent data on using Herceptin plus chemotherapy for treatment of early breast cancer Breast cancer was half as likely to come back in patients who received Herceptin® for a year after completing chemotherapy than in patients who received chemotherapy alone! New England Journal of Medicine, October 20, 2005

30. However, even more exciting is recent data on using Herceptin plus chemotherapy for treatment of early breast cancer The FDA rapidly approved expansion of recommended use FDA News Nov. 16, 2006

31. And back to the pathway…. Farnesyl transferase inhibitors Phase II successes and failures C-1040 Phase II failure Others in Phase I BAY 43-9006 (Phase II) Gilbert Fig. 6.14