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Download CANCER in the third millennium : Pamper the beast
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CANCER in the third millennium : we can beat the beast Science Café Beirut November 27 2008 Tumorigenesis : Multistep theory Normal cell Initial genetic change Secondary genetic change (eg, loss of function of pRb or overexpression of c-myc) (eg, dysfunction of p53 or overexpression of bcl-2) Increase in cell proliferation and apoptosic cell death Decrease in apoptosic cell death Subsequent genetic change Further alterations in phenotype (eg, invasiveness and metastasis) Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134. The doubling process Malignant transformation Dividing Normal cell 4 cells Doubling Doubling 2 cancer cells 8 cells 1 million cells (20 doublings) undetectable Doubling 16 cells 1 trillion cells (40 doublings – 2 lb/1kg) 1 billion cells (30 doublings) lump appears 41 – 43 doublings — Death Tumor growth and detection Number of cancer cells 1012 Diagnostic threshold (1cm) 109 time Undetectable cancer Detectable cancer Limit of clinical detection Host death Pathogenesis MOTILITY & INVASION TRANSFORMATION ANGIOGENESIS Capillaries, Venules, Lymnphatics ADHERENCE ARREST IN CAPILLARY BEDS EMBOLISM & CIRCULATION TRANSPORT Multicell aggregates (Lymphocyte, platelets) EXTRAVASATION INTO ORGAN PARENCHYMA METASTASES RESPONSE TO MICROENVIRONMENT METASTASIS OF METASTASES TUMOR CELL PROLIFERATION & ANGIOGENESIS MALE/CANCER STATISTICS Estimated incidence Estimated deaths Melanoma of skin 3% 2% Melanoma of skin Oral 3% 2% Oral Lung 16% 33% Lung Pancreas 2% 4% Pancreas Stomach 2% 3% Stomach Colon & Rectum 12% 10% Colon & Rectum Prostate 32% 13% Prostate Urinary 9% 5% Urinary Leukemia & Lymphomas 7% 8% Leukemia & Lymphomas All others 14% 20% All others FEMALE/CANCER STATISTICS Estimated incidence Estimated deaths Melanoma of skin 3% 1% Melanoma of skin Oral 2% 1% Oral Breast 32% 18% Breast Lung 13% 23% Lung Pancreas 2% 5% Colon & Rectum 13% 11% Ovary 4% 5% Ovary Uterus 8% 4% Uterus Urinary 4% 3% Urinary Leukemia & Lymphomas 6% 8% Leukemia & Lymphomas All others 13% 21% Pancreas Colon & Rectum All others Most common cancer in the World Nb/100 000 habitants North America North Europe Lung Lung East Europe Lung (Men 74, Women 30) (Men61, Women 19) (Men 64, Women 9) Japan Breast Melanoma (Women 59) (Men 10, Women?) Gastric Prostate Breast (Men 75, Women 35) (Men 31) (Women 85) Prostate Australia New Zeeland (Men 61) Melanoma Liver Colon (Men 21, Women ?) (Men 23, Women 8) (Men 48, Women 37) Colon (Men 45, Women 36) South Africa Breast Cervix (Women 61) (Women 47) Prostate (Men 40) West Africa Cancer statistics in Lebanon NCR reports New cases of Cancer/year Incidence Per 100,000 2003 7142 191.0 2004 7179 179.3 Cancer statistics in Lebanon 2004 men women 1 Lung ( 25.7%) Breast ( 38.2%) 2 Bladder ( 14.6%) Colon ( 7.8% ) 3 Prostate ( 15.4% ) NHL ( 5.9% ) 4 Colon ( 8.6% ) Lung ( 5.9 % ) 5 NHL ( 7.6% ) Ovary ( 4.6% ) Predisposing factors to cancer : Genetic factors : Hereditary Familial Acquired factors : Lifestyle Infectious Physical Chemical Iatrogenic Genetic factors Hereditary Genetic abnormalities Inactivation of Suppressor genes 10 % of cancers Familial syndromes Neurofibromatosis Li-Fraumeni FAP Lynch BRCA1, BRCA2 … 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. 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 Acquired factors Physical agents : Sun Irradiation ( Ex : Hiroshima, Chernobyl … ) Electromagnetism ? Chemical products : Aromatic amines Asbestos Aflatoxin Nitrates … Iatrogenic agents : Radiotherapy Chemotherapy Hormones Specific Lebanese factors tobacco consummation : young age, women, nargile alcohol consummation alimentary fibers High BMI Asbestos at Chekka plant How to reduce mortality Primary prevention: prevent risk factors Secondary prevention : screening, early diagnosis Tertiary prevention : the best therapeutic approach Estimation of mortality reduction Tobacco cessation (primary prevention) Diet change (primary prevention) Screening (secondary prevention) Best treatment (tertiary prevention) 8-16% 8% 3% 20% Tertiary prevention : (Treatment modalities) 1. Surgery 2. Radiotherapy 3. Chemotherapy 4. Immunotherapy 5. Hormonotherapy 6. Targeted therapy 7. Vaccine Tumor classification according to the response to chemotherapy curable sensitive resistant GCT Breast Melanoma HD Ovairy Colon ALL, AML SCLC Hepatocarcinoma NHL NHL NSCLC Pediatric tumors Stomach Glioblastoma Choriocarcinoma Myeloma Sarcomas VEGF Family of Ligands and Receptors VEGF- A121 VEGF- A145 VEGF- A165 VEGF- A189 VEGF- A206 VEGF- B167 VEGF- B186 PlGF- 1,2 VEGF- E VEGF- C VEGF- D Y s-s s-s XX VEGFR1 (Flt-1) NRP-1 Vasculogenesis Angiogenesis VEGFR2 (Flk-1/KDR) VEGFR3 (Flt-4) NRP-2 Lymphangiogenesis Strategies for Blocking VEGFR-2 VEGF VEGF-C Antibody toVEGF-A Blocks ligand binding Blocks receptor activation and signaling VEGF-D VEGF VEGF-C VEGF-D Antibody to VEGFR-2 Blocks ligand binding Blocks receptor activation and signaling VEGF VEGF-C VEGF-D TKI to VEGFR-2 Blocks receptor kinase activation and signaling Avastin mode of action Early effects Continued effects 1 Regression of existing microvasculature Consistent and significant increase in tumour response across treatment regimens (including monotherapy) 3 2 Normalisation of surviving vasculature Potential to combine Avastin with other anticancer agents to maximise clinical outcome Inhibition of new and recurrent vessel growth Extended survival, delay of disease progression, and maintenance of stable disease Effects of Avastin on tumour vasculature and their therapeutic implications HRG (NRG1 ) The EGFR/HER family Ligand binding domain Transmembrane Tyrosine kinase domain Erb-b1 EGFR HER1 neu Erb-b2 HER2 Erb-b3 HER3 Erb-b4 HER4 Mendelsohn J, et al. Oncogene 2000;19:6550–65 Olayioye MA, et al. EMBO J 2000;19:3159–67 EGFR = epidermal growth factor receptor Prigent SA, et al. Prog Growth Factor Res 1992;4:1–24 Harari D, et al. Oncogene 2000;19:6102–14 HER = human epidermal growth Earp HS, et al. Breast Cancer Res Treat 1995;35:115–32 factor receptor Normal HER2 expression HER2 amplification leads to HER2 overexpression HER2 overexpression leads to tumour proliferation Binding of Herceptin to HER2 ® Interaction of MabThera with host immune effector cells CD20 Complement Killer leucocyte Malignant B-cell CD20 MabThera MabThera Adapted from Male DK, et al. Advanced Immunology. 3rd ed. London: Mosby, 1996 The HER family of receptors EGF TGF-a Amphiregulin Betacellulin HB-EGF Epiregulin Heregulins NRG2 NRG3 Heregulins Betacellulin Cysteinerich domains HER1 EGFR erbB1 HER2 erbB2 neu HER3 erbB3 Salomon D, et al. Crit Rev Oncol Hematol 1995;19:183–232 Woodburn J. Pharmacol Ther 1999;82:241–50 HER4 erbB4 Tyrosinekinase domains Effects of anti-EGFR therapy Proliferation Apoptosis Invasion Metastasis Sensitivity to chemotherapy Angiogenesis 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. Tarceva® Adhesion 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 Four examples of screening success ORGAN TEST Cervix cancer Pap smear Incidence Mortality Breast cancer Mammogram Incidence Mortality Colo-rectal cancer Prostate cancer Colonoscopy PSA RESULTS ? ? NCI recommendations TEST AGE Frequency 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 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
