Popperian Pathways: the demarcation between quack cancer cures and scientific remedies. Michael Baum UCL November 2007

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1 Popperian Pathways: the demarcation between quack cancer cures and scientific remedies Michael Baum UCL November 2007

2 The Philosophy of Science:

3 Karl Popper and me 1993

6 Inductive Logic Observations Hypothesis Corroborative Evidence Corroborative Evidence Law of Nature

7 Logical asymmetry between verification and falsification Swans are white Or maybe black

8 If Herbalife truly enhances athletic performance then should it be classified like anabolic steroids?

9 Tectonic plate amulet to neutralize electromagnetic waves

NES Energetic Analysis done by an energy field scanner which shows up organs blocked by anything from environmental and nutritional chemicals to

10 NES Energetic Analysis done by an energy field scanner which shows up organs blocked by anything from environmental and nutritional chemicals to viruses. I'm sure that I need this machine to enable my body's energy fields to re- align themselves and re- activate their innate self- healing abilities".

11 Emotional Freedom Techniques (EFT) is a psychotherapeutic tool. The theory behind EFT is that negative emotions are caused by disturbances in the body's energy field and that tapping on the meridians while thinking of a negative emotion alters the body's energy field, restoring it to balance. EFT

12 Homeopathy The more dilute the evidence the more potent the effect! Homeopathy doesn t poison your body, It poisons your mind

14 The patient was given only 6 months to live but defied the doctor s predictions, took snake oil daily and lived to a ripe old age This is an urban myth, there ain t no such patients.

15 The Patient was only given 6 months to live!

16 The history of the treatment of breast cancer

19 The Ancient World

20 The Edwin Smith Papyrus

23 Ah-ha, ha, you need purgation, bleeding & leeches Yuk! The influence of Galen 200 CE-1840

27 Virchow 1842 Anatomical and Surgical Revolution

28 Halsted s s Hypothesis

29 The Agnew Clinic by Thomas Eakins

32 The Philosophy of Science:

33 Inductive Logic Observations Hypothesis Corroborative Evidence Corroborative Evidence Dogma

35 Popper s s Pathways Observations Thesis Observations Anti-Thesis Experiments Falsification Revised Thesis Anti-Thesis Experiment Falsification Ad Infinitum

36 Clinical Trials Clinical Observations Clinical Observations Thesis Therapy A Anti-Thesis Therapy B Clinical Trial New Clinical Insights Therapy D Therapy C RCT

37 Inconsistencies in the Anatomical Model Impossible to define cure. It returns however perfectly it may be taken away. Lymph node metastases may occur in the absence of an obvious primary. Fisher s mouse models.

38 Bernie Fisher Radical surgery is like slamming the stable door after the horse has bolted We see further because we sit on the shoulders of Giants?Isaac Newton

39 Conceptual Revolutions Paradigm shift : : Thomas Khun

40 Therapeutic consequences: Breast Conservation

41 Anatomical Model Biological Model

42 Breast cancer is a systemic disease Anatomic to Systemic

43 Therapeutic consequences: Breast Conservation Adjuvant Systemic therapy

44 Adjuvant Systemic Therapy Tamoxifen Chemotherapy Anatomical Model Biological Model

48 Comparison of ATAC data with EBCTCG 1995 Overview 1 : Hormone Receptor +ve Patients >50 Estimated % still without recurrence as first event year recurrence-free rate: 92.2% 89.6% 84.6% 70.5% years Control (EBCTCG) Tamoxifen (EBCTCG) Anastrozole (ATAC data) Tamoxifen (ATAC data) 1 EBCTCG. The Lancet 1998; 351:

49 Hmm, I think it s time for another paradigm shift

50 Clinical Inconsistencies in the Anecdotal Biological Model Distant metastases at the time of diagnosis. Hazard rates over time for metastases.

52 % dying within 2 years T1 T 2 T 3 % with metastases at presentation

53 Diagnosis and treatment T 2 T1 TIME

54 Milan data in Disease-Free Survival format Bonadonna, Valagussa et al. NEJM 1995

56 Bimodal relapse pattern observed in mature Milan database (surgery only) Frequency Months from surgery to first recurrence

57 Risk of recurrence peaks in the first 2-3 years following diagnosis 1,2 and is associated with a poor prognosis 3 % hazard of recurrence by yearly interval Node (4+) Tumour size (>3cm) ER Postmen Total Premen ER+ Tumour size ( 1cm) Node Years Adapted from Saphner et al. A meta-analysis of ECOG studies Early Breast Cancer Trialists Collaborative Group. Lancet 1998; 351: Saphner T et al. J Clin Oncol 1996; 14: Rack B et al. Breast Cancer Res Treat 2003; 82:

58 Angiogenesis is Essential for Tumor Growth Beyond 1 2 mm 3, as well as for Metastasis 1 Lymphatics (lymphangiogenesis) Tumor Lymphatic endothelial cell VEGFR3 EPC Bone marrow Fibroblast Tumor-derived VEGF Stromal-derived VEGF VEGFR2 VEGFR1 VEGFR1+ myeloid cells Endothelium (angiogenesis) Endothelial cell Pericyte Tumor growth regulated by a switch to a proangiogenic tumor microenvironment 2,3 1 Folkman. J Natl Cancer Inst 1990;82:4 6 2 Bergers, Benjamin. Nat Rev Cancer 2003;3: Gupta, Zhang. Postgrad Med J 2005;81:

59 Ligand Binding TGF-α Surgery and the new biology HRGs Receptor EGF Receptor Activation Pathway Activation BTC Gene Transcription Proliferation/Maturation Survival Angiogenesis Metastasis

61 Angiostatin X from primary tumour Insulin like Growth Factor Progesterone Apoptotic Cells Tumour Cells Oestrogen Aromatase TGFα COX 2 Her 2 VEGF p53 TGFβ

62 Similarity of gene expression in fibroblasts in response to wounding to those active in Malignant disease. Chang et al PLoS Biol 2004 The way that tumours acquire the ability to create complex tissues does not involve their de novo invention of the complex programme of stromal activation. Instead they activate a latent pre-existing wound healing programme,that is encoded in the normal genome. Weinberg, the Lancet

63 Hypothetical interpretation of Milan data base Induced cell division at surgery months Frequency Induced angiogenesis 10 months Steady stochastic transitions. Natural history months Months from surgery to first recurrence

65 Does Breast Cancer Exist in a state of Chaos? Baum & Chaplain European J Cancer 1999 DCIS

66 Both VEGFR and PDGFR Are Critical for Angiogenesis In pre-clinical studies, sunitinib has been shown to inhibit both VEGFR and PDGFR VEGFR VEGF PDGF PDGFR Vascular endothelial cell Pericyte/fibroblast/ vascular smooth muscle Sunitinib Vascular permeability Cell survival, proliferation, migration Vascular formation, maturation Stable new blood vessels Mendel et al. Clin Cancer Res 2003;9: ; Abrams et al. Mol Cancer Ther 2003;2:

67 Sunitinib Simultaneously Inhibits RTKs on Tumor Cells, Pericytes and Endothelial Cells Antiangiogenic effects Antitumor effects PERICYTE Cross-talk VASCULAR ENDOTHELIAL CELL TUMOR CELL VEGF PDGF VEGF VEGF RTKs expressed by tumor cells PDGFR VEGFR-1 VEGFR-2 VEGFR-3 KIT PDGFRs Sunitinib Sunitinib Sunitinib Sunitinib Multitargeted inhibition results in antiangiogenesis and reversal of tumor growth

68 New therapeutic windows sunitinib DCIS sunitinib

69 " The fact is that one new idea leads to another, that to a third, and so on through the course of time until some one, with whom no one of these ideas was original, combines all together and produces what is justly called a new invention". Thomas Jefferson

70 Traveller, there is no path; the path is made by walking Antonio Machado

71 I can now rejoice even in the falsification of a cherished theory, because even this is scientific success John Carew Eccles Nobel Lauriat for Physiology 1963

72 It is not truisms that science unveils. Rather, it is part of the greatness and the beauty of science that we can learn, through our own critical investigations, that the world is utterly different from what we ever imagined- Popper The Logic of scientific discovery

The Process of Angiogenesis & Inhibition of Angiogenesis and/or Lymphangiogenesis

The Process of Angiogenesis & Inhibition of Angiogenesis and/or Lymphangiogenesis Nam Deuk Kim, Ph.D. Pusan National University Contents Part 1. The process of angiogenesis Part 2. The role of angiopoietins