Transcript CANCER in the third millennium : Pamper the beast

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