21ST CENTURY MEDICINE

Transcription

1 21ST CENTURY MEDICINE TODAY S RESEARCH, TOMORROW S HEALTHCARE SYDNEY MEDICAL SCHOOL CO-PRESENTED WITH SYDNEY IDEAS ROGER REDDEL CURING CANCER: ARE WE NEARLY THERE YET?

2 21ST CENTURY MEDICINE TODAY S RESEARCH, TOMORROW S HEALTHCARE ROGER REDDEL, LORIMER DODS PROFESSOR DIRECTOR, CHILDREN S MEDICAL RESEARCH INSTITUTE CURING CANCER: ARE WE NEARLY THERE YET? SYDNEY MEDICAL SCHOOL CO-PRESENTED WITH SYDNEY IDEAS

3 University of Sydney Fundraising 1920s Christopher Lawrance

4 State of the Union Address 1971 I will also ask for an appropriation of an extra $100 million to launch an intensive campaign to find a cure for cancer, and I will ask later for whatever additional funds can effectively be used. The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease. Let us make a total national commitment to achieve this goal. President Richard Nixon

5 National Cancer Act 1971

6 The war against cancer continues [we] will launch a new effort to conquer a disease that has touched the life of nearly every American, including me, by seeking a cure for cancer in our time President Barack Obama Address to Joint Session of Congress, February 2009

7 Has the war against cancer been lost?

8 Deaths from cancer in USA

9 Has the war against cancer been lost? This year an estimated 121,500 Australians will be told they have cancer now the leading cause of death One in two Australian men and one in three Australian women will be diagnosed with cancer by the age of 85

10 New cases of cancer in Australian females AIHW

11 New cases of cancer in Australian males AIHW

12 Incidence, mortality and 5-year survival for all cancers combined in Australia, 1982 to 2007

13 Incidence, mortality and 5-year survival: Breast cancer in Australia, 1982 to 2007

14 Incidence, mortality and 5-year survival: Bowel cancer in Australia, 1982 to 2007

15 Incidence, mortality and 5-year survival: Brain cancer in Australia, 1982 to 2007

16 What is cancer? One disease or many? What sort of disease? Why has it taken so long to find a cure?

17 Concepts in biology: cells Nerve cell Blood cells The basic building blocks of complex organisms are cells Bone cell

18 Concepts in biology: cells proliferate Cells reproduce themselves to maintain the organism: - programmed replacement of cells that are subject to a lot of wear and tear - replacement of cells damaged by accident

19 Cell proliferation is normally under strict control Cell proliferation is tightly controlled by an intricately orchestrated series of positive and negative signals ( accelerators and brakes )

20 Concepts in biology: DNA contains the instruction set

21 Concepts in biology: DNA contains the instruction set DNA RNA Protein

22 Axel Neumann Human DNA is bundled into 46 chromosomes

23 Concepts in biology: genetic code Most cells have a complete copy of the genetic code, but use only the instructions that are relevant to that cell type Nerve cell Blood cells Bone cell DNA

24 Cancer is caused by damage to genes Cancer is caused by damage to multiple genes - In some cases, some of the damage can be inherited - In all cases, additional genetic damage is found in the cancer cells

25 Types of genes involved in cancer Oncogenes ( accelerators get stuck in the ON position) Tumour suppressor genes ( brakes no longer work) Genes that are normally responsible for genetic stability

26 Cancers caused by infections

27 Cancers evolve as more and more genetic damage accumulates

28 Cancers evolve as more and more genetic damage accumulates Cancers require many key genetic changes Genetic changes occur at random Many are deleterious to the cell and may cause cell death Occasionally genetic change results in selective advantage clonal selection Genetic instability is the engine of carcinogenesis

29 What is cancer? One disease or many? A hundred or more different diseases? But with many features in common

30 Common features of cancer Uncontrolled proliferation Sustained proliferative signalling ( accelerators stuck ON) Evasion of growth suppressors ( brakes OFF) Genetic instability Unlimited replication ( immortality of cancer cells) Resistance to cell death Invasion and spread Development of blood supply Tumour-promoting inflammation Deregulation of cellular energetics Avoiding immune destruction Hanahan and Weinberg, 2011

31 Types of genes involved in cancer Oncogenes ( accelerators get stuck in the ON position) Tumour suppressor genes ( brakes no longer work) Genes that are normally responsible for genetic stability

32 Common features of cancer Uncontrolled proliferation Sustained proliferative signalling ( accelerators stuck ON) Evasion of growth suppressors ( brakes OFF) Genetic instability Unlimited replication ( immortality of cancer cells) Resistance to cell death Invasion and spread Development of blood supply Tumour-promoting inflammation Deregulation of cellular energetics Avoiding immune destruction Hanahan and Weinberg, 2011

33 p53: a key tumour suppressor gene p53 Cell Death Papazoglu and Mills, 2007 Temporary Growth Arrest Permanent Growth Arrest

34 How we know p53 is important in cancer 60% of cancers have mutations in the p53 Many of the remainder have defects elsewhere in the p53 circuitry Cancer-causing viruses make proteins that inactivate p53 Rarely, p53 mutations are inherited and cause a very high cancer risk Removal of the p53 gene from mice makes them highly cancer prone

35 p53: a key tumour suppressor gene MDM2 p53 Cell Death Papazoglu and Mills, 2007 Temporary Growth Arrest Permanent Growth Arrest

36 How we know p53 is important in cancer 60% of cancers have mutations in the p53 Many of the remainder have defects elsewhere in the p53 circuitry Cancer-causing viruses make proteins that inactivate p53 Rarely, p53 mutations are inherited and cause a very high cancer risk 90% in males, 100% in females Often before the age of 30 Often multiple cancers in various organs Removal of the p53 gene from mice makes them highly cancer prone

37 Papazoglu and Mills, 2007 prb: another key tumour suppressor gene

38 How papillomaviruses cause cancer E7 E6

39 Common features of cancer Uncontrolled proliferation Sustained proliferative signalling ( accelerators stuck ON) Evasion of growth suppressors ( brakes OFF) Genetic instability Unlimited replication ( immortality of cancer cells) Resistance to cell death Invasion and spread Development of own blood supply Tumour-promoting inflammation Deregulation of cellular energetics Avoiding immune destruction Hanahan and Weinberg, 2011

40 The ends of chromosomes are called telomeres Cancer cell immortality

41 Cancer cell immortality (TTAGGG)n Telomeres shorten every time normal cells multiply STOP!

42 Cancer cell immortality Cancer cells have all worked out a way to avoid telomere shortening This allows them to keep dividing forever

43 Cancer cell immortality STOP! STOP! Normal! STOP! Cancer! STOP! STOP!

44 Cancer cell immortality STOP! STOP! 90%! Telomerase! Normal! STOP! Cancer! STOP! STOP!

45 Cancer cell immortality STOP! STOP! 90%! Telomerase! Normal! STOP! Cancer! STOP! STOP! 10%! ALT!

46 Cancer cell immortality Tracy Bryan Elizabeth Blackburn

47 Cancer cell immortality A A U C C C A A U C TERT TR Dyskerin Scott Cohen Next: make enough telomerase to take 3D "pictures" Rational drug design

48 Cancer cell immortality STOP! STOP! 90%! Telomerase! Normal! STOP! Cancer! STOP! STOP! 10%! ALT!

49 Hanahan and Weinberg, 2011 The molecular circuitry of cancer

50 Improvements in DNA sequencing $3.8 bn/15 years $4,000/1-2 days

51 Prevention of cancer much better than cure Vaccination against cancer-causing viruses, treatment of H. Pylori Smoking cessation Obesity reduction Reduced exposure to carcinogens such as UV light

52 We can cure cancer already Surgery Importance of early detection

53 We can cure cancer already Surgery Chemotherapy and radiotherapy Testicular cancer Childhood leukaemias Choriocarcinoma Lymphomas When cancers have disseminated widely, there are a few types that can be cured reliably with chemotherapy and/or radiation therapy, but unfortunately these represent only a small percentage of cancers.

54 What do we need to do? Criticisms of the current effort too much emphasis on: - curing laboratory mice - elegant experiments at the expense of searching for cures - understanding everything there is to know about cancer

55 Why is curing cancer so difficult? 1. Cancers arise from our own cells 2. Cancers are genetically unstable

56 Bugs and antibiotics Bacteria Howard Florey Cell wall Penicillin 56

57 Because cancers are genetically unstable, individual cancers are highly heterogeneous

58 What do we need to do? Albert Einstein: If I had an hour to solve a problem I'd spend 55 minutes thinking about the problem and 5 minutes thinking about solutions. How can we get the balance right between further research and acting now on what we know? We spend a lot on treating patients with very imperfect drugs and, by comparison, a relatively small amount on research. Have we got this balance right?

59 Cancer Prevention - what do we need to do? There are things we can sensibly do now, and things that urgently need additional knowledge. For example, we already know that tobacco control and prevention of obesity could prevent cancer, but we need more knowledge about other environmental causes of cancer. We also need much more information about genetic risk profiles and their interaction with environmental factors.

60 What do we need to do? Combinations of Treatments Broad spectrum p53 pathway? Telomerase + ALT inhibitors? Angiogenesis inhibitors? Inhibitors of cancer spread? Tumour-specific Anti-oestrogens Herceptin Imatinib B-RAF inhibitors Treat according to molecular pathways instead of traditional tumour categories?

61 Hanahan and Weinberg, 2011 The molecular circuitry of cancer

62 Is understanding molecular pathways useful? p53: 30 years of research, tens of thousands of research papers, how many cancers have been cured? However: 60% of cancers have mutations in the p53 Many of the remainder have defects elsewhere in the p53 circuitry Cancer-causing viruses make proteins that inactivate p53 Rarely, p53 mutations are inherited and cause a very high cancer risk Removal of the p53 gene from mice makes them highly cancer prone

63 What do we need to do? Constantly keep in mind that we may yet need to discover basic principles that we don t even know exist Maintain appropriate duplication of effort Maintain appropriate competition and collaboration Keep a mix of small research groups and big science

64 Are we nearly there yet? Prediction is very difficult, especially about the future Niels Bohr ( ), Nobel Laureate in Physics

65 Judith Hyam Memorial Trust Fund Acknowledgements