Transcript Jenny T. Mao, MD, FCCP: UCLA Lung Cancer Chemoprevention

UCLA Lung Cancer
Chemoprevention Trials
Jenny T. Mao, M.D., FCCP
Associate Professor
Division of Pulmonary and Critical Care
David Geffen School of Medicine at UCLA
Lung Cancer Statistics
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Leading cause of cancer death in the world.
Estimated 161, 420 lung cancer death in U.S. in
2006. (> coloretal, breast and prostate cancer
combined).
Over 90% caused by smoking.
@ 85% will die within 5 years because most cases
are diagnosed at a late invasive stage.
The lack of effective therapy underscores the
urgency to explore new frontiers of management.
Chemoprevention
Definition
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Chemoprevention is the use of natural or
synthetic agents to reverse, suppress, or prevent
the carcinogenic process to invasive cancer.
--Michael Sporn, M.D., 1976.
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The concept is similar to the use of antihypertensive
and lipid lowering medications to prevent heart disease
or stroke.
Lung Cancer Progression Model- Sequential
Changes During Carcinogenesis
Normal
Hyperplasia
Dysplasia
CIS
3p LOH/small Telomeric deletion
Deletions
Microsatellite Alterations
9p21 LOH
Telomerase Dysregulation
Upregulation
MYC Over-expression
8p21-23 LOH
Neoangiogenesis
Loss of Fhit Immunostaining
P53 LOH
Aneuploidy
Methylation
cancer
3p LOH/Contiguous
~ 50%
~ 70%
Telomerase
TP53 Mutations
5q21 APC-MCC LOH
K-ras Mutation
Hirsch, F et al, 2001, Clin Cancer Res, 7:5-22
~80%
~ 80%
~ 60%
~ 80%
~ 40%
~ 40%
~ 70%
~ 80%
~ 100%
~ 30%
~ 20%
Goals of Chemoprevention
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At the cellular level, inhibit the mechanisms that may
lead to or facilitate malignant transformation.
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At the tissue level, reverse and/or prevent the
development or progression of premalignant lesions.
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At the clinical level, reduce the incidence of cancer.
Growth
factors
Cytokines
Inflammatory
stimuli
Carcinogens
(inducible)
Inflammatory
Sites:
TXA2
• Mf
• Endothelial
cells
Cancer
PGH2
PGE2
• Platelets
COX-1
(constitutive)
• Stomach
• Intestine
• Kidney
PGI2
RATIONALE FOR COX-2 INHIBITION
Celebrex
Tumor Invasiveness
Angiogenesis
Apoptosis
Premalignant
lesions
Cancer
PGE2
Anti-tumor Immunity
IL-10
IL-12
I. Celecoxib for Chemoprevention of
Primary Lung Cancer in Heavy Smokers
High risk cohort:
active smoker > 20 pk-yrs, age >45
Screening
Baseline risk assessment:
1. Questionnaires 3. LIFE Bronch
2. Spirometry
4. CXR
Lung cancer detected
Enrollment
Lung Cancer
detected:
ineligible
Start Treatment with Celecoxib, 400 mg BID
Follow up
Repeat white light bronch at 1
month, LIFE bronch at 6 months.
I. Celecoxib for Chemoprevention of
Primary Lung Cancer
Baseline Subject Characteristics
Mean
Range
Age, yrs
Gender, M/F
Smoking hx (pky)
Ethnicity
54
9/11
42
A/B/C/H
47 - 7
20 -159
1/2/15/2
Family history
COPD
5
10/20
I. Celecoxib for Chemoprevention of
Primary Lung Cancer in Heavy Smoker
Outcome Measures
I.
Modulation of Intra-pulmonary PGE2
production.
II.
BAL cells functional analysis. Antitumor
immunity: balance of IL-10 and IL-12 in the
lung microenvironment.
III.
SEBM: Ki-67 (cellular proliferation),
Histopathology.
RESULTS
Oral administration of Celecoxib inhibits PGE2
synthesis by A23187-stimulated BAL cells
350
Control
A23187
PGE2 (pg/ml)
300
250
200
150
100
50
0
Baseline
1 month
Mao J, et al, Clin Cancer Res. 2003
Freshly isolated BAL
cells before and after
1 month Celecoxib
treatment were
stimulated with
A23187 for 30
minutes. Celecoxib
significantly inhibited
the A23187-induced
PGE2 synthesis. ( p <
0.01, n = 6).
RESULTS
Post-treatment BAL fluid and plasma abrogated
PGE2 production by stimulated NSCLC cells
(A549)
0.5
300
control
250
A23187
200
150
100
50
PGE2(ng/ml)
PGE2 (ng/ml)
350
0.4
0.3
Control
IL-1B
0.2
0.1
0
0
Control
BAL-B
BAL-2
Mao J, et al, Clin Cancer Res. 2003
Control
plasma-B
plasma-2
RESULTS
Inhibition of COX-2 decreased the LPS-induced, upregulation of IL-10 by BAL cells collected from smokers.
1.2
IL-10
(ng/ml)
1
0.8
c
0.6
SC58236
0.4
LPS
0.2
LPS +
SC58236
0
1
2
3
4
5
Mao J, et al, Clin Cancer Res. 2003
6
7
8
9
10
Effects of Celecoxib on Histopathology of
Bronchial Biopsies in Smokers
*
Grade
1 - Normal
2 - Hyperplasia
3 - Squamous
metaplasia
4 - Mild
Dysplasia
n = 100
Mao J, et al, Clin Cancer Res. 2006
Ki-67
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Ki-67 is a proliferation marker expressed in all
phases of the cell cycle except in resting cells.
Abnormal epithelial proliferation is a hallmark
of tumorigenesis.
Elevated Ki-67 expression is associated with
poor prognosis.
Elevated Ki-67 levels can be detected in areas
where squamous metaplasia is lacking.
Ki-67 may be a useful marker for lung cancer
risk.
Level of Ki-67 correlated with smoking history
A
B
*
20
Ki-67 LI
P = 0.032
10
0
0
25
Mao J, et al, Clin Cancer Res. 2006
50
pky
75
100
6 months of Celecoxib reduced Ki-67 LI by 35%.
Baseline
Ki-67 Labeling Index
12
10
8
*
6
4
2
0
Baseline
Final
Mao J, et al, Clin Cancer Res. 2006
Final
Summary
from the Phase IIa Smokers Study
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Oral Celecoxib blocked the capacity of PGE2 production
by smokers’ AM.
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Plasma and BAL fluid obtained from treated subjects
blocked PGE2 production by stimulated NSCLC cells
A549 in vitro.
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Inhibition of COX-2 blocked the release of IL-10 by LPS
stimulated AM from smokers, may restore anti-tumor
immunity.
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Oral Celecoxib decreased Ki-67 LI in bronchial biopsies,
indicating that celecoxib may be capable of favorably
modulating the proliferation indices in bronchial tissue
of active smokers.
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These findings support the continued investigation of
COX-2 inhibitor in lung cancer chemoprevention.
II. Lung Cancer Chemoprevention
with Celecoxib in Ex-Smokers
Overall Objectives
 To determine the feasibility of Celecoxib for
chemoprevention of lung cancer in high risk exsmokers. Celecoxib is being evaluated for its impact
on cellular and molecular events associated with
lung carcinogenesis:
1) modulation of a panel of biomarkers of field
cancerization,
2) regulation of arachidonic acid metabolism,
3) antitumor immunity
4) angiogenesis in the lung microenvironment.
II. Lung Cancer Chemoprevention
with Celecoxib in Ex-Smokers
Former smokers, > 30 pk-yrs, age >45;
Stage I NSCLC post curative resection
Screening
Baseline risk assessment:
1. Questionnaires
2. Spirometry
3. Sputum induction 4. LIFE Bronch
5. Spiral CT
6. Buccal smear
7. Blood
8. Urine collection.
Lung Cancer
detected:
ineligible
Enrollment
1:1 Randomization
Stratification: 1. Prior stage I NSCLC.
Follow up 2. preneoplasia
II. Lung Cancer Chemoprevention
with Celecoxib in Ex-Smokers
1:1 Randomization
6 months placebo
6 months Celebrex
Repeat LIFE bronch, buccal
smear, blood, urine and
CROSSOVER
questionnaires at 6 mo.
6 months placebo
CROSSOVER
6 months Celebrex
Repeat LIFE bronch, CT,
buccal smear, blood, urine
and questionnaires at 12 mo.
RECRUITMENT FLOWCHART
Total Number of Inquiries
4,006
Ineligible*
2,099
Ineligible****
164
Walk-In Screen
297
Enrolled
120
Pending**
52
In Process
13
Declined***
1,558
Laboratory Studies and SEBM
1. Bronchial biospsies
Immunostaining: Ki-67, COX-2,
EGFR, p16, p27, cyclin D1 & E, bcl-2,
p53, CD44,
Histopathology
Frozen biopsy: CXC chemokines.
RNA from homogenates.
DNA analysis : GSTP1, p16
methylation. GSTP1, GSTM1,
CYP1A1, P53 polymorphisims.
2. BAL
Fluid: PGE2, IL10, IL-12, VGEF, CXC
chemokines, MMP, TIMP-1, LTB4
Cytology
Alveolar Macrophages:
1.Functional analysis. 2. RNA
3. Sputum:
Cytology
Immunostaining
4. Blood
Plasma: PGE2
Buffy coat
5. Buccal Smear
DNA analysis
6.
Urine
7.
Primary Tumor:
Cox-2
Buccal Cell Genotyping
~ 137 SNP genotyping assays were performed using
the Applied Biosystems SNPlex assay.
Total # subjects with
baseline buccal cell assayed
135
without
bronch
61
normal path on
bronchial biopsy
41
Squamous
metaplasia
33
Buccal Cell genotyping
After adjusting for age, sex, race, education levels,
income and pack-years of smoking, an association
between abnormal bronchial biopsy with the
following polymorphisms was found :
NBS1 (DNA repair gene: HRR pathway)
NBS1 rs1063053 (p = 0.0162)
NBS1 rs1063054 (p = 0.0231)
NBS1 rs2735383 (p = 0.0231)
NBS1 rs9995 (p = 0.0514)
ADPRT (DNA repair gene: BER pathway)
ADPRT rs1805414 (p=0.0319)
Acknowledgement
Division of Pulmonary
& Critical Care
S. Dubinett B. Adams
M. Roth
J. Bailow
R. Strieter F. Baratelli
D. Tashkin M. Burdick
J . Dermand
T. Ho
M. Hoang
V. Nguyen
D. Ritter
A. Tsu
L. Ying
L. Zhu
Thoracic Surgery
E.C. Holmes
R. Cameron
S. Perez
Thoracic Imaging
D. Aberle
Pathology
M. Fishbein
J.Y. Rao
Oncology
R. Figlin
Biostatistics
Epidemiology
R. Elashoff
H-J. Wang
Z-F. Zhang
UCSD
K. Serio
C Chun
W. Cao
SUPPORT
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TRDRP
CRFA
NCI/K23
NCI/UO1
UCLA Lung Cancer SPORE
Stop Cancer Miller Family Grant
Study drugs from Pfizer, Inc.