Science Café Beirut November 27 2008 CANCER in the third millennium : we can beat the beast.
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Transcript of Science Café Beirut November 27 2008 CANCER in the third millennium : we can beat the beast.
Science Café Beirut
November 27 2008
CANCER in the third millennium :
we can beat the beast
Tumorigenesis :Tumorigenesis :Multistep theoryMultistep theory
Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134.
Initialgenetic change(eg, loss of function of pRb or overexpression of c-myc)
Decreasein apoptosiccell death
Subsequentgenetic change
Normalcell
Increase incell proliferationand apoptosiccell death
Secondarygenetic change(eg, dysfunction of p53or overexpression of bcl-2)
Further alterationsin phenotype(eg, invasivenessand metastasis)
The doubling processThe doubling process
NormalNormalcellcell
DividingDividing
MalignantMalignanttransformationtransformation
2 cancer2 cancercellscells
DoublingDoubling 4 cells4 cells
DoublingDoubling
8 cells8 cells
DoublingDoubling
16 cells16 cells
1 million cells1 million cells(20 doublings)(20 doublings)undetectableundetectable
1 billion cells1 billion cells(30 doublings)(30 doublings)lump appearslump appears
1 trillion cells1 trillion cells(40 doublings – 2 lb/1kg)(40 doublings – 2 lb/1kg)
41 – 4341 – 43doublingsdoublings— Death— Death
Tumor growth and detectionTumor growth and detection
10101212
101099
timetime
DiagnosticDiagnosticthresholdthreshold(1cm)(1cm)
UndetectableUndetectablecancercancer
DetectableDetectablecancercancer
Limit ofLimit ofclinicalclinicaldetectiondetection
HostHostdeathdeath
Nu
mb
er
of
Nu
mb
er
of
can
cer
cells
can
cer
cells
PathogenesisPathogenesis
TRANSFORMATION ANGIOGENESISMOTILITY & INVASION
Capillaries,Venules, Lymnphatics
ADHERENCE
ARREST INCAPILLARY BEDS EMBOLISM &
CIRCULATION
EXTRAVASATIONINTO ORGANPARENCHYMA RESPONSE TO
MICROENVIRONMENT
TUMOR CELLPROLIFERATION& ANGIOGENESIS
METASTASES
METASTASIS OFMETASTASES
TRANSPORT
Multicell aggregates(Lymphocyte, platelets)
MALE/CANCER STATISTICSMALE/CANCER STATISTICS
Estimated incidence Estimated deaths
Melanoma of skinMelanoma of skin
OralOral
LungLung
PancreasPancreas
StomachStomach
Colon & RectumColon & Rectum
ProstateProstate
UrinaryUrinary
Leukemia & LymphomasLeukemia & Lymphomas
All othersAll others
3%3%
3%3%
16%16%
2%2%
2%2%
12%12%
32%32%
9%9%
7%7%
14%14%
Melanoma of skinMelanoma of skin
OralOral
LungLung
PancreasPancreas
StomachStomach
Colon & RectumColon & Rectum
ProstateProstate
UrinaryUrinary
Leukemia & LymphomasLeukemia & Lymphomas
All othersAll others
2%
2%
33%
4%
3%
10%
13%
5%
8%
20%
1%1%
1%1%
18%18%
23%23%
5%5%
11%11%
5%5%
4%4%
3%3%
8%8%
21%21%
FEMALE/CANCER STATISTICSFEMALE/CANCER STATISTICS
Estimated incidence Estimated deaths
Melanoma of skinMelanoma of skin
OralOral
BreastBreast
LungLung
PancreasPancreas
Colon & RectumColon & Rectum
OvaryOvary
UterusUterus
UrinaryUrinary
Leukemia & LymphomasLeukemia & Lymphomas
All othersAll others
3%3%
2%2%
32%32%
13%13%
2%2%
13%13%
4%4%
8%8%
4%4%
6%6%
13%13%
Melanoma of skinMelanoma of skin
OralOral
BreastBreast
LungLung
PancreasPancreas
Colon & RectumColon & Rectum
OvaryOvary
UterusUterus
UrinaryUrinary
Leukemia & LymphomasLeukemia & Lymphomas
All othersAll others
Most common cancer in the WorldNb/100 000 habitants
North AmericaLung
(Men 74, Women 30)Melanoma
(Men 10, Women?)Breast
(Women 85)Prostate(Men 61) Colon
(Men 48, Women 37)
North EuropeLung
(Men61, Women 19)Breast
(Women 59)Prostate(Men 31)
West AfricaLiver
(Men 23, Women 8)
South AfricaCervix
(Women 47)
East EuropeLung
(Men 64, Women 9) JapanGastric
(Men 75, Women 35)
Australia New ZeelandMelanoma
(Men 21, Women ?)Colon
(Men 45, Women 36)Breast
(Women 61)Prostate(Men 40)
Cancer statistics in LebanonNCR reports
New cases ofCancer/year
IncidencePer 100,000
2003 7142 191.0
2004 7179 179.3
Cancer statistics in Lebanon2004
men women1 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 factorsHereditary Genetic abnormalities Inactivation of Suppressor genes 10 % of cancers
Familial syndromes Neurofibromatosis Li-Fraumeni FAP Lynch BRCA1, BRCA2 …
Acquired factorsLife 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 factorsInfectious 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 factorsPhysical 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 mortalityPrimary prevention: prevent risk factors
Secondary prevention : screening, early diagnosis
Tertiary prevention : the best therapeutic approach
Estimation of mortality reduction
Tobacco cessation(primary prevention)
8-16%
Diet change(primary prevention)
8%
Screening(secondary prevention)
3%
Best treatment(tertiary prevention)
20%
Tertiary prevention : (Treatment modalities)
1. Surgery2. Radiotherapy3. Chemotherapy4. Immunotherapy5. Hormonotherapy6. Targeted therapy7. Vaccine
Tumor classification according to the response to chemotherapy
curable sensitive resistantGCT Breast Melanoma
HD Ovairy Colon
ALL, AML SCLC Hepatocarcinoma
NHL NHL NSCLC
Pediatric tumors Stomach Glioblastoma
Choriocarcinoma Myeloma Sarcomas
s-s
VEGF- B167
VEGF- B186
PlGF- 1,2
VEGF- A121
VEGF- A145
VEGF- A165
VEGF- A189
VEGF- A206
VEGF- EVEGF- CVEGF- D
VEGFR1(Flt-1)
VEGFR2(Flk-1/KDR)
VEGFR3(Flt-4)
NRP-1
s-s
NRP-2
Vasculogenesis
Angiogenesis
Lymphangiogenesis
YYYYXX XX
VEGF Family of Ligandsand Receptors
Strategies forBlocking VEGFR-2
Antibody to VEGFR-2Antibody to VEGFR-2 Blocks ligand bindingBlocks ligand binding Blocks receptor activationBlocks receptor activation
and signalingand signaling
TKI to VEGFR-2TKI to VEGFR-2 Blocks receptor kinaseBlocks receptor kinase
activation and signalingactivation and signaling
VEGF
VEGF-C VEGF-D VEGF VEGF-D VEGF VEGF-C VEGF-DVEGF-C
Antibody to VEGF-A
Blocks ligand binding
Blocks receptor activationand signaling
Avastin mode of action
Regression of existing microvasculatureConsistent and significant increase in tumour response across treatment regimens (including monotherapy)
Normalisation of surviving vasculaturePotential to combine Avastin with other anticancer agents to maximise clinical outcome
1
2
Inhibition of new and recurrent vessel growthExtended survival, delay of disease progression, and maintenance of stable disease
3
Early effects Continued effects
Effects of Avastin on tumour vasculature and their therapeutic implications
Erb-b1EGFRHER1
neu Erb-b2HER2
Erb-b3HER3
Erb-b4HER4
TG
F
EG
F
Ep i -ce
l
Am
p
Ep
i
HB
-GF
NR
G1
NR
G2
NR
G3
NRG4
Tyrosinekinase
domain
Ligandbindingdomain
Transmembrane
Mendelsohn J, et al. Oncogene 2000;19:6550–65Olayioye MA, et al. EMBO J 2000;19:3159–67
Prigent SA, et al. Prog Growth Factor Res 1992;4:1–24Harari 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
-EG
F
HR
G(N
RG
1)
The EGFR/HER family
Normal HER2 expression
HER2 amplification leads toHER2 overexpression
HER2 overexpression leads totumour proliferation
Binding of Herceptin® to HER2
Interaction of MabThera with host immune effector cells
Adapted from Male DK, et al. Advanced Immunology. 3rd ed. London: Mosby, 1996
MalignantB-cell
CD20
MabTheraMabThera
CD20
ComplementKillerleucocyte
The HER family of receptors
HER1EGFRerbB1
HER2erbB2neu
EGFTGF-
AmphiregulinBetacellulin
HB-EGFEpiregulin Heregulins
NRG2NRG3
HeregulinsBetacellulin
Cysteine-rich
domains
Tyrosine-kinase
domains
HER3erbB3 HER4
erbB4
Salomon D, et al. Crit Rev Oncol Hematol 1995;19:183–232Woodburn J. Pharmacol Ther 1999;82:241–50
Tarceva®
Proliferation
Invasion
MetastasisAngiogenesis
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.
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 RESULTS
Cervix cancer Pap smear Incidence
Mortality
Breast cancer Mammogram Incidence
Mortality
Colo-rectal cancer Colonoscopy ?
Prostate cancer PSA ?
NCI recommendationsTEST 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 smokingNo alcohol abuse Eat healthy ( less animal fat, more fibers)
Avoid sun expositionAvoid weight excessPhysical activities : jogging, running