1. Cancer: Are we closer to a cure? Thanks to: 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… Deaths per 100,000 people Year CDC Mortality Data

4. 2015: A unprecedented moment in the history of cancer Before BRAF drug 6 weeks later Example: BRAF-mutant melanoma 2015: A unprecedented moment in the history of cancer

5. How did this happen? Identification in 2002 that the BRAF protein is mutated in melanoma Develop a powerful drug that blocks the BRAF protein Launch a focused clinical trial by enrolling only patients with molecular biomarker that predicts response (sequence tumor) Understand relationship between having the mutation and responding to therapy Clinical trials are thus smaller, faster and cheaper See amazing clinical success (~2009) and FDA approval (2011)

6. Before Iressa treatmentAfter 3 months of Iressa treatment We have made HUGE advances in other cancers!!!! Image provided by B. Johnson

7. 2003201120152023 Empiric/ Experimental (organ) Precise/ Targeted (gene) Personalized (patient) Progress/The Future: Two decades of cancer medicine

8. Discovering Cancer Genes where we are now Mapping cancer genes highlights potential drug targets Human genome mapped in 2001 First cancer genome decoded in 2009 2014: Broad has mapped over 15,000 cancer genomes across >25 tumor types, produced the world’s standard computational tools We will soon have the complete map of common mutations in every major cancer type Major discoveries in nearly every cancer type; genome-guided medicine becoming reality for patients

9. Many cancer patients today are having their tumor genomes sequenced to predict treatments patienttumor clinical sequencing and pathology mutations (10-150) cancer drugs that each target one of the mutations We don’t have all of the drugs yet, but now that we know what proteins to block, drug companies are developing successful cancer drugs at a much faster pace!

10. We have also made HUGE advances in prevention!!!!

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

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

13. An Uncontrolled Growth of Cells 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!...................................... structural support dividing cells non-dividing cells normal skin skin cancer

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

15. 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

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

17. 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

18. Facts: Smoking and Alcohol Cigarette smoking causes 87 percent of lung cancer deaths and is responsible for most cancers of the larynx, oral cavity 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

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

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

21. What Happens Normally? DNA Bases Normal DNA AT CG CG AT CG AT C G A A T T

22. What Happens Normally? AT CG CG AT CG AT C G A C G A G A C mRNA DNA is transcribed (copied) to RNA A A T T A A

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

24. AT CG CG AT CG Changed DNA AT CG DELETION A Mutation Occurs AT

25. Changed DNA A Mutant Protein is Made AT CG CG AT CG AT CG A C G A G A C Changed mRNA DELETION Normal Protein Abnormal/ Mutant Protein AT A A A AT

26. A Mutant Protein is Made Normal Protein Changed DNA A T CG CG AT CG CG A T Abnormal/ Mutant Protein AT AT

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

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

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

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

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

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

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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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 normal cellcancer cell mutations 1 2 3 4 5 6…..

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

41. 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

42. 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)

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

44. Cancer treatment Tumor Lung Heart

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

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

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

48. The problem of Selectivity of chemotherapy and radiation Why need targeted therapy? cancer cellsnormal cells

49. The problem of Selectivity of chemotherapy and radiation Why need targeted therapy? cancer cellsnormal cells

50. The problem of Selectivity of chemotherapy and radiation Why need targeted therapy? cancer cellsnormal cells

51. Killing a fly with a cannon ball?

52. We can kill the fly but…

53. 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 cancer cellsnormal cells

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

55. Goal: Discover new drugs that attack most important mutations Example: MCL1 gene helps cells survive Progress: Discovery of new early stage drugs that block MCL1 in cancer cells normalbreast cancer MCL1 gene ALIVEDEAD Turn off MCL1 in lab

56. Goal: Discover new drugs that attack most important mutations Example: MCL1 gene helps cells survive Want to explore this further? Check this out: Progress: Discovery of new early stage drugs that block MCL1 in cancer cells 500,000 chemicalsrobotics http://www.hhmi.org/biointeractive/bcr-abl-cancer-protein-structure-function

57. 2015 Revolution in Cancer Therapy #1: Using the immune system to fight cancer Amazing, unpredecented successes (2013- 2015), never before seen! A revolution in cancer therapy

58. 2015 Revolution in Cancer Therapy #2: Resurrect “failed” drugs by finding genes that allowed rare patients to respond!

59. Can you have an impact on cancer? He did!

60. Points to remember Cancer is a family of similar diseases, not just one!  Different cancers have different causes, treatments and outcomes Cancer is caused by MUTATIONS Prevent your exposure to mutagens! A tumor causes a patient harm by becoming malignant and metastasizing By learning more about cancer we are developing new, “smarter” cancer drugs  More effective  Fewer side effects