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Cancer Chemoprevention

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Cancer Chemoprevention & Biomarkers JianYu Rao, M.D. Prof. Of Pathology/Epidemiology UCLA – PowerPoint PPT presentation

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Title: Cancer Chemoprevention


1
Cancer Chemoprevention Biomarkers
  • JianYu Rao, M.D.
  • Prof. Of Pathology/Epidemiology
  • UCLA

2
CANCER PREVENTION
  • PRIMARY
  • STOP THE EXPOSURE
  • SECONDARY
  • INTERVENTION
  • TERTIARY
  • TREATMENT

3
CANCER INTERVENTION Treating premalignant
lesions
  • Surgical/procedure
  • Castration / Oophorectomy
  • Polypectomy
  • Colposcopy
  • Non-surgical (CHEMOPREVENTION)
  • Nutritional/chemical
  • Immuno (BCG)
  • Vaccine
  • Molecular targeted
  • Behavioral
  • Smoking cessation

4
S Lippman, Cancer Res. 2009 Jul 169(13)5269-84
5
A Most Successful Cancer Control Story in 20th
Century
Colposcopy CONE/LEEP
Pap Test
Detect Early Lesions
Treat Early Lesions
Decreased incidence/ mortality of cervical CA
6
CHEMOPREVENTION
  • Administrating specific amounts of a particular
    natural or synthetic chemical in an attempt to
    identify agents that will prevent, halt or
    reverse the process of carcinogenesis
  • The basic assumption is that treating early
    stages of malignant process will halt the
    progression of malignancy
  • The key is to define early lesions, and treat the
    malignant field

7
Additional Molecular Event
Exposure to Carcinogen
Precancerous Intraepithelial Lesions, (PIN,
CIN, PaIN..)
Cancer
Birth
CHEMOPREVENTION
8
Multiyear progression from initiation and early
precancerous lesions to invasive disease in major
cancer target organs
Kelloff et al. 2000 (Fig. 1)
9
THEORIES SUPPORT FOR CHEMOPREVENTION
  • EPIDEMIOLOGICAL EVIDENCE
  • OVER 50 CANCERS HAVE NO KNOWN RISK FACTORS
  • NUMEROUS EVIDENCE TO DEMONSTRATE THE INVERSE
    RELATIONSHIPS OF SOME NUTRIENT FACTORS WITH
    CANCER RISKS

10
THEORIES SUPPORT FOR CHEMOPREVENTION (Cont.)
  • EXPERIMENTAL EVIDENCE
  • ALTHOUGH CARCINOGENESIS IS REGARDED AS
    NONREVERSIBLE PROCESS, STUDIES SHOWED THIS IS
    ONLY TRUE AT LATE STAGE. IN FACT, A LARGE
    PORTION OF THE LONG LATENCY PERIOD OF
    CARCINOGENIC PROCESS IS REVERSIBLE.
  • IN VITRO CULTURE AND IN VIVO ANIMAL STUDIES
    IDENTIFIED NUMEROUS AGENTS THAT CAN REVERSE, OR
    HALT THE CARCINOGENESIS PROCESS, PARTICULARLY AT
    THE EARLY STAGE.

11
THEORIES SUPPORT FOR CHEMOPREVENTION (Cont.)
  • CLINICALLY
  • ADVANCES IN CERTAIN TYPES OF CANCER TREATMENT
    HAVE LIMITED SUCCESS IN REDUCING THE OVERALL
    INCIDENCE, OR EVEN MORTALITY OF CANCER.

12
Chemoprevention Some Terminologies
  • INDIVIDUAL RISK AND STRATIFICATION
  • INTERMEDIATE END POINT MARKER (SURROGATE END
    POINT MARKER)
  • FIELD CANCERIZATION
  • MULTI-PATH OF CARCINOGENESIS

13
RISK STRATIFICATION
  • Identification of AT-RISK subjects who are also
    SUSCEPTIBLE to treatment

14
INTERMEDIATE END POINT MARKER (SURROGATE END
POINT MARKER)
  • These are prevention biomarkers which are
    specifically related to early stages of
    carcinogenesis.
  • These markers are used to identify individuals
    risk for developing cancer and to monitor the
    effectiveness of intervention methods.

15
FIELD CANCERIZATION
  • The whole field of tissue of a particular organ
    is exposed to the carcinogenic insult and is at
    increased risk for developing cancer.
  • Although only a few foci eventually develop
    malignancy, the other areas are not necessary
    entirely normal.
  • Most common epithelia cancers are developed
    through this mechanism. Examples of such cancers
    are Head and neck ca, bladder ca, breast ca,
    lung ca, GI ca, etc.

16
MULTI-PATH OF CARCINOGENESIS
  • The current model of carcinogenesis is that
    cancer develops through multiple events which are
    not necessary through linear steps, but rather
    through overlapping networks.

17
CHEMOPREVENTION IN DIFFERENT RISK CATEGORIES
Risk category
Parameter
General Population High Risk
Agent toxicity Trivial to none Slight Selectio
n method Public Health Clinical Other
consideration Use dietary supplements Need
biomarkers may be applicable
From lee W. Wattenberg, P.S.E.B.M., 1997
216133-141.
18
Phase I Trial
  • Objectives
  • To determine the interventions short-term (lt1
    yr.) dose-toxicity relationship
  • To determine the interventions human
    pharmacokinetics
  • Design
  • Single arm, nonrandomized
  • Multiple dose levels
  • Less than 1 yr. duration
  • Accrual 25-100

19
Phase II Trial
  • Objectives
  • To determine the interventions side effects
  • To determine optimal recruitment methods of the
    target population
  • To determine retention of study participants to
    the study intervention and procedures
  • To determine optimal methods for the conducting
    of a phase III trial
  • To determine the effect of the intervention on
    biomarkers of carcinogenesis (phase II b)
  • Design
  • Randomized, double-blind, placebo-controlled
  • Multiple dose levels or agents
  • One to five years in duration
  • Accrual 100s-1000s

20
Phase III Trial
  • Objectives
  • To determine the effect of the intervention on
    the cancer incidence (total and specific cancer
    type)
  • To determine the effect of the intervention on
    death rate and disease incidence
  • To determine the long-term side effects of the
    intervention
  • To determine the nature history of specific
    biomarkers of carcinogenesis (placebo group) and
    the effect of the intervention agent (treatment
    group) on these markers.
  • Design
  • Randomized, double-blind, placebo-controlled
  • Multiple dose levels or agents, alone or in
    combination
  • Five to ten years in duration
  • Accrual 1000s-10,000s

21
UNIQUE FEATURES OF CHEMOPREVENTION
  • Participants are usually healthy or at least
    cancer free
  • The degree and incidence of side effects that are
    acceptable are low
  • The end point is disease prevention, not disease
    response
  • The incidence of the study end point is low

22
CATEGORIES OF CHEMOPREVENTIVE AGENTS
  • BLOCKING CARCINOGEN METABOLISM AND EXPOSURE
  • INCREASE TISSUE RESISTANCE/DIFFERENTIAITON
  • TARGETING ONCOGENIC PATHWAYS

23
CATEGORIES OF CHEMOPREVENTIVE AGENTS
  • BLOCKING AGENTS
  • Prevent metabolic activation of carcinogens or
    tumor promoters
  • Enhance detoxification
  • Glutathione-S-transferase
  • Trap reactive carcinogenic species
  • Glutathione, N-Acetylcysteine
  • Vaccines HBV, HPV

24
CATEGORIES OF CHEMOPREVENTIVE AGENTS (Cont.)
  • INCREASING TISSUE RESISTANCE
  • Induce tissue maturation/differentiation
  • Pregnancy or hormonal induced maturation of
    terminal ducts of breast - decrease breast cancer
  • Retinoids, DMFO, etc
  • Decrease target tissue function
  • Castration - reduce risk of prostate ca
  • Decrease cell proliferation
  • Low fat diet decrease epithelial proliferation
    rate in intestinal tract - reduce colon cancer
    risk

25
CATEGORIES OF CHEMOPREVENTIVE AGENTS (Cont.)
  • PATHWAY SPECIFIC AGENTS
  • Cox-2 inhibitors
  • Anti-angiogenesis
  • Anti-EGFR
  • Hormone antagonists
  • Augmenting tumor suppressor functions
  • Inhibiting oncogenic activities (e.g., Ras)

26
BRIDGING THE GAP BETWEEN CANCER TREATMENT AND
PREVENTION (William WN, et al, Nat Rev Drug
Discov. 2009 Mar8(3)213-25.)
27
CHEMOPREVENTION TO HUMANS - UPDATE
  • BREAST CANCER
  • Selective Estrogen Receptor Modulator (SERM)/STAR
    Trial
  • Animal model well established
  • PROSTATE CANCER
  • SCID model established
  • Hormonal modulation may have potential
  • PCPT Trial Finasteride (5-a-reductase, 5mg/day)
  • 2-arm trial, 18,882 subjects, 7 yrs
  • PCP18.4 vs 24.8 in treated vs ctrl group
  • Selenium/Vit E Trial - negative

28
STAR TRIAL
  • STAR The Study of Tamoxifen (20 mg/day) and
    Raloxifene (60 mg/day) for breast cancer
    prevention
  • A Phase III trial involving over 50 centers and
    19,747 high risk women age 35 or above
  • Both drugs reduced the risk of developing
    invasive breast cancer by about 50 percent.
  • In addition, women who took raloxifene daily had
    36 percent fewer uterine cancers and 29 percent
    fewer blood clots than the women who took
    tamoxifen.

29
SELECT TRIAL (Lippman, et al, JAMA, 2009)
  • SELECT Selenium and Vitamin E Cancer Prevention
    Trial
  • A Phase III trial involving over 400 sites and
    35533 men, age gt50 (for AA) or gt55 (others)
  • 4 groups (selenium, vitamin E, selenium vitamin
    E, and placebo) in a double-blind fashion between
    August 22, 2001, and June 24, 2004
  • No significant differences (all Pgt.15) in
    prostate cancer end points

30
CHEMOPREVENTION TO HUMANS - UPDATE (CONT.)
  • GASTRIC AND ESOPHAGEAL CANCER
  • A combination of beta carotene, vitamin E, and
    selenium may be effective in early stage lesions,
    but not late severe dysplastic lesions.
  • LUNG CANCER
  • Beta-carotene or alpha-tocopherol showed reverse
    effect in lung cancer risk in heavy smokers in
    Finland
  • Ongoing trials with COX-2 inhibitor in former
    smokers here at UCLA

31
CHEMOPREVENTION TO HUMANS - UPDATE (CONT.)
  • COLON CANCER
  • Sulindac, a nonsteroidal anti-inflammatory
    compound hold great promise. Others, such as
    Oltiparz, selenium, and antioxidants vit. E/A,
    etc, may also be effective. Large trials are not
    available.
  • HEAD AND NECK CANCER
  • Retinoids showed promising results in both animal
    models and human studies.

32
SUMMARY (CHEMOPREVENTION)
  • Chemoprevention is an important approach for
    cancer control
  • The goal is to treat premalignant lesions
  • Successful stories include cervix, breast,
    prostate, head and neck
  • Less successful stories include lung, colon, etc
  • No magic single bullet, but new molecular
    targets show greater promise than traditional
    nutritional regimens

33
BIOMARKERS OF CANCER
  • CLINICAL SETTINGS (TUMOR MARKERS)
  • EPIDEMIOLOGICAL AND PREVENTIVE SETTINGS
    (INTERMEDIATE END POINT OR SURROGATE END POINT
    MARKERS).

34
CURRENT CLINICALLY USED TUMOR MARKERS
  • PSA - Prostate Adenocarcinoma
  • Alpha FP - Hepatoma seminoma
  • HCG - Choriocarcinoma
  • CEA - Colon cancer
  • CA19.9 Pancreatic cancer
  • CA125 Ovarian cancer
  • Problem Low sensitivity/specificity

35
BIOMARKERS
  • Genetic susceptibility markers
  • Markers of exposure
  • Markers of biological effects
  • Tumor markers

36
Additional Molecular Event
Exposure to Carcinogen
Precancerous Intraepithelial Lesions, (PIN,
CIN, PaIN..)e
Cancer
Birth
Surrogate End Point Markers
Markers for Exposure
Markers of Effect
Tumor Markers
Genetic Suscep. Marker
CHEMOPREVENTION
37
HOW TUMOR MARKERS ARE USED CLINICALLY
  • Early detection and diagnosis
  • Predict the biological potential of cancer
    (prognostication)
  • Determine who will be likely benefited from the
    therapy (phamacocogenetic / pharmacogenomic)
  • Monitor the effectiveness of therapy

38
CRITERIA FOR SELECTING BIOMARKER
  • FITS EXPECTED BIOLOGICAL MECHANISM
  • BIOMARKER AND ASSAY PROVIDE ACCEPTABLE
    SENSITIVITY, SPECIFICITY, AND ACCURACY
  • BIOMARKER IS EASILY MEASURED
  • BIOMARKER MODULATION CORRELATES TO THE END POINT
  • Disease incidence (for detection marker)
  • Disease progression (for prognostic marker)
  • Response to therapy (for therapeutic marker)

39
ASSAY VALIDITY
  • SENSITIVITY
  • of assay-positive cases in case group
  • SPECIFICITY
  • of assay-negative cases in control group
  • PPV (Positive Predictive Value)
  • of true assay-positive cases out of all
    assay-positive cases
  • NPV (Negative Predictive Value)
  • of true assay-negative cases out of all
    assay-negative cases

These numbers can be totally meaningless always
know what kind of design used (case-control vs
cohort) and what is the gold standard
40
OTHER ASSAY ISSUES
  • BIOMARKER CAN BE OBTAINED BY NON-INVASIVE
    TECHNIQUES
  • ASSAY IS NOT TECHNICALLY DIFFICULT
  • MULTIPLE MARKERS CAN BE EVALUATED SIMULTANEOUSLY
    IN LIMITED SAMPLE VOLUMES
  • COST

41
CATEGORIES OF MARKERS
  • HISTOLOGICAL AND MORPHOMETRIC MARKERS
  • PROLIFERATION, DIFFERENTIATION AND INVASION
    MARKERS
  • PATHWAYS SPECIFIC MARKERS
  • MARKERS OF GENETIC AND EPIGENETIC INSTABILITY

42
Issues in Using Biomarker
  • The observed change may not correlate with end
    point (cancer incidence, response to therapy,
    etc).
  • Can not measure the quality of life.
  • Adverse effect may not be observed in short term
    biomarker studies.

43
High Throughput Techniques
  • Array technology (-omics)
  • DNA chips
  • cDNA array format
  • in situ synthesized oligonucleotide format
    (Affymetrix)
  • Proteomics
  • Tissue arrays
  • These are powerful tools and high throughput
    methods to fish-out biomarker targets, but they
    are not the answers themselves
  • Individual targets/patterns identified need to be
    validated

44
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45
Proteomics
  • Examine protein level expression in a high
    throughput manner
  • Used to identify protein markers/patterns
    associated with disease/function
  • Different formats
  • SELDI-TOF (laser desorption ionization
    time-of-flight) the protein-chip arrays, the
    mass analyzer, and the data-analysis software
  • 2D Page coupled with MALDI-TOF (matrix-assisted
    laser desorption ionization time-of-flight)
  • Antibody based formats

46
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47
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48
A, GTE (20?g/ml)
pI
9
MW (kDa)
8
8
9
2
2
1
1
5
5
11
10
11
13
13
10
7
17
6
7
6
17
18
16
16
18
12
12
14
14
3
3
15
15
4
4
B, GTE (40?g/ml)
pI
20
19
MW (kDa)
1
1
5
10
5
11
11
13
17
17
13
10
18
12
18
16
16
12
14
14
15
15
4
Time
48 hr
48 hr
24 hr
-


GTE
49
Tissue Array
  • Provide a new high-throughput tool for the study
    of gene dosage and protein expression patterns in
    a large number of individual tissues for rapid
    and comprehensive molecular profiling of cancer
    and other diseases, without exhausting limited
    tissue resources.
  • A typical example of a tissue array application
    is in searching for oncogenes amplifications in
    vast tumor tissue panels. Large-scale studies
    involving tumors encompassing differing stages
    and grades of disease are necessary to more
    efficiently validate putative markers and
    ultimately correlate genotypes with phenotypes.
  • Also applicable to any medical research
    discipline in which paraffin-embedded tissues are
    utilized, including structural, developmental,
    and metabolic studies.

50
Bladder Array
Gelsolin
HE
51
Lessons learned from SELDI-TOF
  • Initial study on patient serum from cancer
    patients (ovarian, prostate, etc) versus cancer
    showed very promising results (nearly 100
    sensitivity/specificity to separate cancer from
    normal)
  • Used case-control design
  • Only 2 group-comparison (cancer vs. normal)
  • No validation
  • However, recent validation studies were rather
    disappointing

52
Biomarker-Directed Targeted Design
  • Increase the efficiency of the trial, but
    depends on
  • The performance of the biomarker test
    (sensitivity/specificity)
  • Size of the treatment effect for target-negative
    patients

53
BIOMARKER STUDY DSEIGN
a. Untargeted Design
Treatment
Register
Randomize
Control
b. Untargeted Design
Treatment
Biomarker
Test Biomarker
Randomize
Register
Control
54
BIOMARKER STUDY DSEIGN
Biomarker by Treatment Interaction Design
Treatment
Biomarker
Randomize
Control
Test Biomarker
Stratify
Register
Treatment
Biomarker -
Randomize
Control
55
BIOMARKER STUDY DSEIGN
Biomarker Based Strategy Design
Biomarker
Treatment A
Test Biomarker
Biomarker -
Treatment B
Register
Randomize
No Biomarker Evaluation
Treatment B
56
BIOMARKER STUDY DSEIGN
Modified Biomarker Based Strategy Design
Biomarker
Treatment A
Test Biomarker
Biomarker -
Treatment B
Register
Randomize
Treatment A
No Biomarker Evaluation
Randomize
Treatment B
57
GENETIC SUSCEPTIBILITY MARKERS
  • Genome Wide Association (GWA) studies help to
    identified genetic markers for cancer
  • Prostate Chromosome 8q24 (Gudundsson, et al,
    Nature genetics/Yeager, et al, Nature Genetics,
    2007)
  • Lung Chromosome 15q25 (nicotinic acetylcholine
    receptor subunits) (Huang, et al, Nature
    2008/Amos, et al, Nature Genetics,
    2008/Thorgerisson, et al, Nature genetic, 2008)
  • Genes identified in these locus may also be the
    targets for chemopreventive drug development

58
SUMMARY
  • No magic single marker, or a pattern of marker,
    that will address all issues about cancer
  • Know exactly what the marker is used for, and the
    criteria/gold standard for marker may be
    different
  • Early detection - precancer lesion
  • Diagnosis - cancer
  • Therapeutic selection/monitoring - response
  • Prognostic indication - progression
  • -omics is a useful commodity to find marker.
    However, more simplified method should be used to
    detect marker clinically

59
Thank You!!!
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