RTKs and rational cancer therapy - PowerPoint PPT Presentation

omer
slide1 l.
Skip this Video
Loading SlideShow in 5 Seconds..
RTKs and rational cancer therapy PowerPoint Presentation
Download Presentation
RTKs and rational cancer therapy

play fullscreen
1 / 64
Download Presentation
RTKs and rational cancer therapy
210 Views
Download Presentation

RTKs and rational cancer therapy

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. RTKs and rational cancer therapy Dr Andrejs Liepins/Science Photo Library

  2. Are we making progress?

  3. In looking at “5-year” survival, we need to remember we are are making a LOT of progress in cancer detection for some cancers

  4. And we need to remember detection when it comes to “survival rates”

  5. How does current chemotherapy work?

  6. KILL dividing cells!

  7. Chemotherapy Kills all dividing cells Amanda Dugger 2007 ACS Hero of Hpe

  8. There has to be a better way! Amanda Dugger 2007 ACS Hero of Hpe

  9. Let’s go Back to the 1970s Bishop and Varmus

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

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

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

  13. And that was just a few of the RTK families doi:10.1016/j.cell.2010.06.011

  14. The EGF receptor family Adding complexity, In mammals many RTKs and ligands Are encoded by Multi-gene families Valberga, Anals. Oncogene 07

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

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

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

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

  19. 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

  20. While HER2 is overexpressed in some neuroblastomas, it is not commonly mutated there “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

  21. However, it did provide the earliest example of a mutated RTK in a tumor

  22. It also allowed Cori Bargmann to make a bold prediction

  23. "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"

  24. She was right! "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"

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

  26. Here’s a cool example A chimeric oncogenic version of the trk RTK was isolated from a human colon carcinoma Lodish et al. Fig. 24-16

  27. 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

  28. However, mutational activation of RTKs in human tumors is rare

  29. So why are you telling us all this?

  30. 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

  31. HER2 is Amplified in 30% of Breast Cancer Cases HER2 normal HER2 amplified Kim et al, JKMS 08

  32. This and other RTKs are amplified in other cancers EGFR amplified in some glioblastomas and lung cancers Met amplified in drug resistance lung cancers HER2 amplified in some bladder cancers Kit amplified in some gastrointestinal stromal tumors

  33. They are enzymes--what should we do?

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

  35. Iressa, an EGFR inhibitor Illustrates the ups And downs Of this form of therapy aka Gefitinib

  36. Iressa 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

  37. Iressa 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 raised serious questions about whether it prolongs life. Curr Treat Options Oncol. 2005 6:75-81 www.iressa-us.com

  38. Data suggested that Iressa benefits a small subset of patients Including “never-smokers” and Patients of Asian descent Curr Treat Options Oncol. 2007 Feb;8(1):28-37

  39. Data suggested that Iressa benefits a small subset of patients Including “never-smokers” and Patients of Asian descent Why those patients? Curr Treat Options Oncol. 2007 Feb;8(1):28-37

  40. It only works on patients with activating mutations in the kinase domain of the EGF receptor

  41. It has been partially replaced by Erlotinib (Tarceva), another EGFR inhibitor approved for “second line” treatment of non-small cell lung cancer

  42. Erlotinib (Tarceva) works, but how well? Median Survival: 6.7 months vs. 4.7 months in placebo control

  43. 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

  44. Even when kinase inhibitors work well initially....

  45. Relapses often occur

  46. Relapses often occur How could that happen?

  47. Have you heard The one about Natural selection?

  48. Second site mutations in kinase block drug binding Or other RTKs (e.g., c-Met) are gene amplified

  49. Luckily drugs are not the only approach