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Science Café Beirut November 27 2008 CANCER in the third millennium : we can beat the beast.

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Presentation on theme: "Science Café Beirut November 27 2008 CANCER in the third millennium : we can beat the beast."— Presentation transcript:

1 Science Café Beirut November CANCER in the third millennium : we can beat the beast

2 Tumorigenesis : Multistep theory Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997; Initial genetic change (eg, loss of function of pRb or overexpression of c-myc) Decrease in apoptosic cell death Subsequent genetic change Normal cell Increase in cell proliferation and apoptosic cell death Secondary genetic change (eg, dysfunction of p53 or overexpression of bcl-2) Further alterations in phenotype (eg, invasiveness and metastasis)

3 The doubling process Normal cell Dividing Malignant transformation 2 cancer cells Doubling 4 cells Doubling 8 cells Doubling 16 cells 1 million cells (20 doublings) undetectable 1 billion cells (30 doublings) lump appears 1 trillion cells (40 doublings – 2 lb/1kg) 41 – 43 doublings — Death

4 Tumor growth and detection time Diagnostic threshold (1cm) Undetectable cancer Detectable cancer Limit of clinical detection Host death Number of cancer cells

5 Pathogenesis TRANSFORMATIONANGIOGENESIS MOTILITY & INVASION Capillaries, Venules, Lymnphatics ADHERENCE ARREST IN CAPILLARY BEDS EMBOLISM & CIRCULATION EXTRAVASATION INTO ORGAN PARENCHYMA RESPONSE TO MICROENVIRONMENT TUMOR CELL PROLIFERATION & ANGIOGENESIS METASTASES METASTASIS OF METASTASES TRANSPORT Multicell aggregates (Lymphocyte, platelets)

6 MALE/CANCER STATISTICS Estimated incidenceEstimated deaths Melanoma of skin OralLungPancreasStomach Colon & Rectum ProstateUrinary Leukemia & Lymphomas All others 3%3%16%2%2%12%32%9%7%14% Melanoma of skin OralLungPancreasStomach Colon & Rectum ProstateUrinary Leukemia & Lymphomas All others 2% 33% 4% 3% 10% 13% 5% 8% 20%

7 1%1%18%23%5%11%5%4%3%8%21% FEMALE/CANCER STATISTICS Estimated incidenceEstimated deaths Melanoma of skin OralBreastLungPancreas Colon & Rectum OvaryUterusUrinary Leukemia & Lymphomas All others 3%2%32%13%2%13%4%8%4%6%13% Melanoma of skin OralBreastLungPancreas Colon & Rectum OvaryUterusUrinary Leukemia & Lymphomas All others

8 Most common cancer in the World Nb/ habitants North America Lung (Men 74, Women 30) Melanoma (Men 10, Women?) Breast (Women 85) Prostate (Men 61) Colon (Men 48, Women 37) North Europe Lung (Men61, Women 19) Breast (Women 59) Prostate (Men 31) West Africa Liver (Men 23, Women 8) South Africa Cervix (Women 47) East Europe Lung (Men 64, Women 9) Japan Gastric (Men 75, Women 35) Australia New Zeeland Melanoma (Men 21, Women ?) Colon (Men 45, Women 36) Breast (Women 61) Prostate (Men 40)

9 Cancer statistics in Lebanon NCR reportsNew cases of Cancer/year Incidence Per 100,

10 Cancer statistics in Lebanon 2004 menwomen 1Lung ( 25.7%)Breast ( 38.2%) 2Bladder ( 14.6%)Colon ( 7.8% ) 3Prostate ( 15.4% )NHL ( 5.9% ) 4Colon ( 8.6% )Lung ( 5.9 % ) 5NHL ( 7.6% )Ovary ( 4.6% )

11 Predisposing factors to cancer : Genetic factors : Hereditary Familial Acquired factors : Lifestyle Infectious Physical Chemical Iatrogenic

12 Genetic factors Hereditary Genetic abnormalities Inactivation of Suppressor genes 10 % of cancers Familial syndromes Neurofibromatosis Li-Fraumeni FAP Lynch BRCA1, BRCA2 …

13 Acquired factors Life Style : Smoking : cause 50% of cancers 90% of cancer pts are smokers lung, H&N, bladder, cervix 25x lung cancer Alcohol : H&N, esophagus, liver, bladder Nutrition : high fat + low fibers cause colon and breast cancer Physical activities : regular physical exercises reduce breast cancer. weight excess increases breast cancer risk.

14 Acquired factors Infectious agents : Bilharzias Bladder cancer Malaria NHL EBV Burkitt, UCNT Hepatitis Hepatocarcinoma Papilloma virus Cervix cancer AIDS Kaposi, NHL, Cervix HTLV1 Adult T cell LL Helicobacter Stomach cancer

15 Acquired factors Physical agents : Sun Irradiation ( Ex : Hiroshima, Chernobyl … ) Electromagnetism ? Chemical products : Aromatic amines Asbestos Aflatoxin Nitrates … Iatrogenic agents : Radiotherapy Chemotherapy Hormones

16 Specific Lebanese factors tobacco consummation : young age, women, nargile alcohol consummation alimentary fibers High BMI Asbestos at Chekka plant

17 How to reduce mortality Primary prevention: prevent risk factors Secondary prevention : screening, early diagnosis Tertiary prevention : the best therapeutic approach

18 Estimation of mortality reduction Tobacco cessation (primary prevention) 8-16% Diet change (primary prevention) 8% Screening (secondary prevention) 3% Best treatment (tertiary prevention) 20%

19 Tertiary prevention : (Treatment modalities) 1. Surgery 2. Radiotherapy 3. Chemotherapy 4. Immunotherapy 5. Hormonotherapy 6. Targeted therapy 7. Vaccine

20 Tumor classification according to the response to chemotherapy curablesensitiveresistant GCTBreastMelanoma HDOvairyColon ALL, AMLSCLCHepatocarcinoma NHL NSCLC Pediatric tumorsStomachGlioblastoma ChoriocarcinomaMyelomaSarcomas

21

22 s-s VEGF- B 167 VEGF- B 186 PlGF- 1,2 VEGF- A 121 VEGF- A 145 VEGF- A 165 VEGF- A 189 VEGF- A 206 VEGF- E VEGF- C VEGF- D VEGFR1 (Flt-1) VEGFR2 (Flk-1/KDR) VEGFR3 (Flt-4) NRP-1 s-s NRP-2 Vasculogenesis Angiogenesis Lymphangiogenesis Y Y XX VEGF Family of Ligands and Receptors

23 Strategies for Blocking VEGFR-2 Antibody to VEGFR-2 Blocks ligand binding Blocks ligand binding Blocks receptor activation and signaling Blocks receptor activation and signaling TKI to VEGFR-2 Blocks receptor kinase activation and signaling Blocks receptor kinase activation and signaling VEGF VEGF-C VEGF-D VEGF VEGF-D VEGF VEGF-C VEGF-D VEGF-C Antibody to VEGF-A Blocks ligand binding Blocks receptor activation and signaling

24 Avastin mode of action Regression of existing microvasculature Consistent and significant increase in tumour response across treatment regimens (including monotherapy) Normalisation of surviving vasculature Potential to combine Avastin with other anticancer agents to maximise clinical outcome 1 2 Inhibition of new and recurrent vessel growth Extended survival, delay of disease progression, and maintenance of stable disease 3 Early effectsContinued effects Effects of Avastin on tumour vasculature and their therapeutic implications

25 Erb-b1 EGFR HER1 neu Erb-b2 HER2 Erb-b3 HER3 Erb-b4 HER4 TGF  EGF Ep i  -cel Amp Epi HB-GF NRG1 NRG2 NRG3 NRG4 Tyrosine kinase domain Ligand binding domain Transmembrane Mendelsohn J, et al. Oncogene 2000;19:6550–65 Olayioye MA, et al. EMBO J 2000;19:3159–67 Prigent SA, et al. Prog Growth Factor Res 1992;4:1–24 Harari D, et al. Oncogene 2000;19:6102–14 Earp HS, et al. Breast Cancer Res Treat 1995;35:115–32 EGFR = epidermal growth factor receptor HER = human epidermal growth factor receptor HB-EGF HRG (NRG1 ) The EGFR/HER family

26 Normal HER2 expression

27 HER2 amplification leads to HER2 overexpression

28 HER2 overexpression leads to tumour proliferation

29 Binding of Herceptin ® to HER2

30 Interaction of MabThera with host immune effector cells Adapted from Male DK, et al. Advanced Immunology. 3rd ed. London: Mosby, 1996 Malignant B-cell CD20 MabThera CD20 Complement Killer leucocyte

31 The HER family of receptors HER1 EGFR erbB1 HER2 erbB2 neu EGF TGF-  Amphiregulin Betacellulin HB-EGF Epiregulin Heregulins NRG2 NRG3 Heregulins Betacellulin Cysteine- rich domains Tyrosine- kinase domains HER3 erbB3 HER4 erbB4 Salomon D, et al. Crit Rev Oncol Hematol 1995;19:183–232 Woodburn J. Pharmacol Ther 1999;82:241–50

32  Tarceva ®  Proliferation  Invasion  Metastasis  Angiogenesis  Apoptosis  Adhesion  Sensitivity to chemotherapy Effects of anti-EGFR therapy  Moyer J, et al. Cancer Res 1997;57:4838–48. Pollack V, et al. J Pharmcol Exp Ther 1999;291:739–48. Data on file, OSI Pharmaceuticals Inc.

33 Secondary prevention : (screening) Mass early detection in asymptomatic persons by a specific tool 4 diseases : Cervix …. Pap smear Breast …. Mammogram Prostate …. PSA Colon …. Colonoscopy Early detection often increases cure rate

34 Four examples of screening success ORGANTESTRESULTS Cervix cancerPap smear Incidence Mortality Breast cancerMammogram Incidence Mortality Colo-rectal cancerColonoscopy? Prostate cancerPSA?

35 NCI recommendations TESTAGEFrequency Pap smear> 18/ year Gaiac> 50/ year RDE> 40 ? Colonoscopy> 50 ? PSA> 50/ year Mammogram> 50 (40)/ year Breast autopalpation> 20/ month Clinical breast exam> 40/ year

36 Primary prevention : (Reduce risk factors) Quit smoking No alcohol abuse Eat healthy ( less animal fat, more fibers) Avoid sun exposition Avoid weight excess Physical activities : jogging, running


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