Cancer: Are we closer to a cure?

1. Cancer: Are we closer to a cure? Jesse Boehm, Ph.D. Broad Institute of Harvard and MIT Cambridge, MA

2. Cancer is a huge public health problem

3. Overall mortality rates have not changed for cancer… * Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2001 Mortality Data–NVSR-Death Final Data 2001–Volume 52, No. 3. http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf

4. But we have made HUGE advances in some cancers!!!! Before Iressa treatment After 3 months of Iressa treatment Image provided by B. Johnson

5. …and we are on the verge of many more successes!!!!

6. We have made HUGE advances in prevention!!!!

7. The Fundamentals of Cancer • What is cancer? • Molecular causes of cancer • How faulty genes are involved • How a cancer cell becomes dangerous

8. What is Cancer? • An uncontrolled growth of cells • A genetic disease • A family of similar diseases newscenter.cancer.gov

9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . An Uncontrolled Growth of Cells normal skin skin cancer non-dividing cells dividing cells structural support • Healthy cells turn into the enemy • divide too quickly or abnormally • become abnormal shapes and sizes • grow in all directions • Cells stop listening to the body, which is telling them to stop!

10. . . . . . . . . . . . . . . . . . . . . A Genetic Disease Normal Cells Cancer Cells • Mutations in DNA can make normal cells become cancerous • These can be inherited or spontaneous

11. A Family of Similar Diseases • Carcinomas: from cells which • protect the body from air • and internal fluids • Sarcomas: from cells in • supportive tissue • Leukemias and Lymphomas: • from cells in the blood and • immune system newscenter.cancer.gov

12. The Fundamentals of Cancer • What is cancer? • Molecular causes of cancer • How faulty genes are involved • How a cancer cell becomes dangerous

13. Common causes of cancer • Chemicals (e.g. tobacco, asbestos) • Viruses (e.g. HPV) • Radiation from the sun • What do all of these have in common? • They all lead to MUTATIONS • in the DNA of your cells • They are called MUTAGENS • Can also be predisposed to getting cancer by inheriting mutations from parents newscenter.cancer.gov

14. Smoking and Alcohol • Cigarette smoking causes 87 percent of lung cancer deaths and is responsible for most cancers of the larynx, oralcavity and pharynx, esophagus, and bladder • Tobacco smoke contains thousands of chemical agents, including over 60 substances that are known to cause cancer. • Alcohol use has been implicated in the development of a number of cancers • Risk increases >1 drink for women or 2 drinks for men/day

15. Causes of Cancer What are mutations and how do they cause normal cells to become cancer cells? Cancer Cells

16. How Could a Mutant Protein Make Cells Divide Out of Control? ? mutant protein cancer cells mutant DNA

17. A A A A A T T T T T G G G G C C C C What Happens Normally? Normal DNA DNA Bases

18. A A A A A A A A T T T T T G G G G G G C C C C C C What Happens Normally? Normal DNA mRNA DNA is transcribed (copied) to RNA A A

19. A A A A A A A A T T T T T G G G G G G C C C C C C What Happens Normally? Normal DNA mRNA Normal Protein amino acids Translation: Proteins are made from mRNA A A

20. A A A A T T T T G G G G C C C C A Mutation Occurs Changed DNA DELETION

21. A A A A A T T T T T G G G G G G C C C C C C A Mutant Protein is Made Changed DNA Changed mRNA Normal Protein A A DELETION A A Abnormal/ Mutant Protein A A

22. A A A A A T T T T T G G G G C C C C A Mutant Protein is Made Changed DNA Normal Protein Abnormal/ Mutant Protein

23. How Could a Mutant Protein Make Cells Divide Out of Control? ? mutant protein cancer cells

24. The Cell Cycle Controls Cell Division Cells divide (mitosis) Growth Cell Cycle Growth DNA Synthesis

25. The Cell Makes Sure That There are no Problems Did division go correctly? Cell Cycle Am I ready to divide? Am I big enough? Is my DNA copied correctly?

26. The Cell Cycle Has Checkpoints Did division go correctly? Cell Cycle Am I ready to divide? Am I big enough? Is my DNA copied correctly?

27. The Normal Protein Functions at a Cell Cycle Checkpoint Cell Cycle Normal Protein Is my DNA copied correctly?

28. The Mutant Protein Allows The Cell to Divide Out of Control Cell Cycle Normal Protein go! Abnormal/ Mutant Protein I can’t stop and check if the DNA has been copied correctly!!!

29. The Fundamentals of Cancer • What is cancer? • Molecular causes of cancer • How faulty genes are involved • How a cancer cell becomes dangerous

30. How Faulty Genes are Involved • Not every gene leads to cancer when mutated • Mutations in two specific categories of genes can lead to cancer • Tumor-Suppressor Genes • Oncogenes

31. How Faulty Genes are Involved • Not every gene leads to cancer when mutated • Mutations in two specific categories of genes can lead to cancer • Tumor-Suppressor Genes • Oncogenes

32. Inactivated Tumor Suppressor Genes Lead to Cancer • Tumor Suppressor (TS) genes normally inhibit cell growth • Mutations in TS genes may inactivate them, • so that they cannot stop cell-growth • TS genes include p53 and BRCA1/2 cell TS gene

33. How Faulty Genes are Involved • Not every gene leads to cancer when mutated • Mutations in two specific categories of genes can lead to cancer • Tumor-Suppressor Genes • Oncogenes

34. Activated Oncogenes Lead to Cancer • Oncogenes normally promote cell growth carefully • Mutations in oncogenes may over-activate them, • so that they always promote cell-growth • One well-known oncogene is called RAS cell oncogene

35. RAS RAS p53 p53 Mutations in Specific Genes Turn a Normal Cell into a Cancer Cell Mutate tumor suppressor genes, turning these genes OFF Mutate oncogenes, turning these genes ON 1 2 3 4 5 6….. mutations normal cell cancer cell

36. The Fundamentals of Cancer • What is cancer? • Molecular causes of cancer • How faulty genes are involved • How a cancer cell becomes dangerous

37. Benign vs. Malignant Benign: A non-malignant tumor lacking the ability to invade surrounding normal tissue Malignant: A tumor that tends to grow, has the capacity to invade nearby tissue and spreads through the blood stream adapted from “Concise Dictionary of Biomedicine and Molecular Biology,” Pei-Show Juo, 1996

38. How cancer cells become dangerous • A cancer cell on its own will not cause you harm • To become the disease “Cancer” the cell must: • 1) Form a tumor (at least) • 2) Recruit a blood supply • = angiogenesis • (solid tumors only) • 3) Spread to other parts of the body • = metastasis • (advanced stages)

39. Metastasis Cancer cells enter blood vessels Cells travel through the blood stream to distant sites Cells then invade new tissues, and begin to grow

40. Tumor Cancer treatment Heart Lung

41. There are different types of treatments Drugs (chemotherapy) Radiation Surgery

42. Cancer can be local or metastatic local (one primary tumor) metastatic (secondary tumors)

43. Cancer therapy: local and systemic Rx LOCAL: surgery and radiation SYSTEMIC: chemotherapy, etc.

44. Why need targeted therapy? • The problem of Selectivity of chemotherapy and radiation normal cells cancer cells

45. Why need targeted therapy? • The problem of Selectivity of chemotherapy and radiation normal cells cancer cells

46. Why need targeted therapy? • The problem of Selectivity of chemotherapy and radiation normal cells cancer cells

47. Killing a fly with a cannon ball?

48. We can kill the fly but…

49. Problem with selectivity leads to side effects •  SIDE EFFECTS! • hair follicles: hair loss • bone marrow:  immune defense, anemia, clotting problems • gut lining: diarrhea • skin: flaky/scaly skin normal cells cancer cells

50. Normal cell How can we improve cancer therapy? • Pick a better TARGET! Cancer cell