1. Molecular Biology of Cancer

2. CANCER TAKES TIME

3. CANCER IS A DISEASE OF GENETIC MUTATIONS ACCUMULATION OF MANY MUTATIONS CAUSES CANCER

4. YOU MUST REMEMBER THAT ALL MUTATIONS ARE RANDOM YOU WILL MUTATE DRIVERS AND PASSENGERS

5. WHAT MAKES A CANCER CELL A CANCER CELL? UNLIMITED GROWTH UNLIMITED MOVEMENT

7. Growth Factors int-2 sis Growth Factor Receptors erbB-1 fms kit met erbB-2 Cytoplasmic Kinases src bcr-abl fes lck yes Nuclear Proteins ets fos jun myc FGF PDGF EGF-R CSF-1R Stem Cell GF-R Hepatic GF-R Heregulin R FAMOUS ONCOGENES

9. The Cell Cycle

11. FAMILIAL CANCER SYNDROMES Li-Fraumeni p53 Deleted in Pancreas Smad4 Retinoblastoma Rb Breast Cancer Brca1,2 Wilms Tumor WT1 Nonpolyposis Colon MSH2,MLH1 Neurofibromatosis 1,2 NF1,NF2 von Hippel-Lindau VHL Adenomatous Polyposis APC Melanoma INK4a/ARF Cowden Disease PTEN Gorlin PTCH Multiple Endocrine Neoplasia MEN1

12. THE DEFINITION OF A TUMOR SUPPRESSOR Classical Features: 1.Loss of function mutations 2.Targeted allelic loss- Methylation or Deletion 3.Inherited mutations that predispose to cancer 4.Somatic mutation in spontaneous tumors 5.Ability to inhibit transformed cells in vitro

15. ACTIVATING THE p53 RESPONSE

16. p53 Modifications

17. ACCESSING THE CELL CYCLE MACHINERY

18. The Ink4a/Arf Locus

21. 11 11 11 11 3 3 2 CpG DE-REPRESSION ONCOGENES RAS PRC1 PRC2 ARF INK4A

22. SELECTIVE PRESSURE THROUGH STRESS From environment: -Low oxygen -Low nutrients -Radiation -Ligands From self: -Random mutant -ROS -Grow too fast Dealing with it: -Arrest/Senesce -Apoptosis MUTATE

23. Not just division…But growth

25. Understanding what translation is really all about Growth signals PI-3k/mTOR Pathway And Regulators of Ribosome biogenesis 60S 40S 5’ AAAAAAAAAA-3 ’ UTR Active translationRibosome biogenesis rRNA synthesis rRNA processing rRNA export

26. PI3K GFR Akt Rheb Ras mTOR Tuberin/ Hamartin PTEN Neurofibromin Tuberous sclerosis complex Neurofibromatosis type 1 (NF1) Cowden Syndrome Lhermitte-Duclos disease S6KeIF4E NPM ARF p68

27. THINKING ABOUT TRANSLATION

28. THE NUCLEOLUS NPM ARF

29. MAKING RIBOSOMAL RNA

31. Micro RNA

32. PUTTING IT ALL TOGETHER 1. IDENTIFY THE MUTATIONS 2. SEPARATE DRIVERS FROM PASSENGERS 3. FIND DRUGGABLE TARGETS4. TEST IT ON THE RIGHT PATIENTS