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