Jenny T. Mao, M.D., FCCP
Associate Professor
Division of Pulmonary and Critical Care
David Geffen School of Medicine at UCLA
UCLA Lung Cancer UCLA Lung Cancer Chemoprevention TrialsChemoprevention Trials
UCLA Lung Cancer UCLA Lung Cancer Chemoprevention TrialsChemoprevention Trials
Lung Cancer StatisticsLung Cancer Statistics
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 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.
The concept is similar to the use of antihypertensive and lipid lowering medications to prevent heart disease or stroke.
3p LOH/small Telomeric deletion 3p LOH/ContiguousDeletions
~80%
Microsatellite Alterations ~ 50%9p21 LOH ~ 70%
Telomerase Dysregulation TelomeraseUpregulation
~ 80%
MYC Over-expression ~ 60% 8p21-23 LOH ~ 80%
Neoangiogenesis ~ 40%Loss of Fhit Immunostaining ~ 40%P53 LOH TP53 Mutations ~ 70%Aneuploidy ~ 80%Methylation ~ 100%
5q21 APC-MCC LOH ~ 30%K-ras Mutation ~ 20%
Lung Cancer Progression Model- Sequential Changes During Carcinogenesis
Hirsch, F et al, 2001, Clin Cancer Res, 7:5-22
Normal Hyperplasia Dysplasia CIS cancer
Goals of Chemoprevention
At the cellular level, inhibit the mechanisms that may lead to or facilitate malignant transformation.
At the tissue level, reverse and/or prevent the development or progression of premalignant lesions.
At the clinical level, reduce the incidence of cancer.
AA PGG2
PGD2
PGF2
COX-2
COX-1
(constitutive)
Carcinogens
TXA2
PGH2
• Platelets
• Stomach
• Intestine
• Kidney
Inflammatory Sites:
• M• Endothelial cells
Cancer
(inducible)
PGI2
Inflammatorystimuli
Growthfactors Cytokines
PGE2
RATIONALE FOR COX-2 INHIBITIONRATIONALE FOR COX-2 INHIBITION
Celebrex
Premalignant
lesions
Cancer
Angiogenesis Apoptosis
Anti-tumor Immunity
PGE2
IL-10 IL-12
Tumor Invasiveness
I. Celecoxib for Chemoprevention of I. Celecoxib for Chemoprevention of Primary Lung Cancer in Heavy SmokersPrimary Lung Cancer in Heavy Smokers
Screening
Lung cancer detected
Enrollment
Follow up
High risk cohort: active smoker > 20 pk-yrs, age >45
Baseline risk assessment: 1. Questionnaires 3. LIFE Bronch 2. Spirometry 4. CXR
Lung Cancer detected: ineligible
Start Treatment with Celecoxib, 400 mg BID
Repeat white light bronch at 1 month, LIFE bronch at 6 months.
I. Celecoxib for Chemoprevention of I. Celecoxib for Chemoprevention of Primary Lung CancerPrimary Lung Cancer
Baseline Subject Characteristics
Mean Range
Age, yrs 54 47 - 7Gender, M/F 9/11 -Smoking hx (pky) 42 20 -159Ethnicity A/B/C/H 1/2/15/2
Family history 5COPD 10/20
I. Celecoxib for Chemoprevention of I. Celecoxib for Chemoprevention of Primary Lung Cancer in Heavy SmokerPrimary 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.
RESULTSRESULTS
Oral administration of Celecoxib inhibits PGE2 synthesis by A23187-stimulated BAL cells
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).
0
50
100
150
200
250
300
350
Baseline 1 month
PG
E2
(pg
/ml)
Control
A23187
Mao J, et al, Clin Cancer Res. 2003
RESULTSRESULTS
Post-treatment BAL fluid and plasma abrogated PGE2 production by stimulated NSCLC cells
(A549)
0
50
100
150
200
250
300
350
Control BAL-B BAL-2
PG
E2
(ng
/ml)
control
A23187
0
0.1
0.2
0.3
0.4
0.5
Control plasma-B plasma-2PG
E2(n
g/m
l)
Control
IL-1B
Mao J, et al, Clin Cancer Res. 2003
0
0.2
0.4
0.6
0.8
1
1.2
1 2 3 4 5 6 7 8 9 10
c
SC58236
LPS
LPS +SC58236
IL-10 (ng/ml)
Inhibition of COX-2 decreased the LPS-induced, up-regulation of IL-10 by BAL cells collected from smokers.
Mao J, et al, Clin Cancer Res. 2003
RESULTSRESULTS
Effects of Celecoxib on Histopathology of
Bronchial Biopsies in Smokers*
Mao J, et al, Clin Cancer Res. 2006
Grade
1 - Normal
2 - Hyperplasia
3 - Squamous metaplasia
4 - Mild
Dysplasia
n = 100
Ki-67Ki-67
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
Mao J, et al, Clin Cancer Res. 2006
A
*
0 25 50 75 1000
10
20
pky
Ki-
67 L
I
B P = 0.032
6 months of Celecoxib reduced Ki-67 LI by 35%.
Mao J, et al, Clin Cancer Res. 2006
0
2
4
6
8
10
12
Baseline Final
Ki-
67
Labelin
g I
ndex
Baseline
*
Final
Summary Summary from the Phase IIa Smokers Studyfrom the Phase IIa Smokers Study
Oral Celecoxib blocked the capacity of PGE2 production by smokers’ AM.
Plasma and BAL fluid obtained from treated subjects blocked PGE2 production by stimulated NSCLC cells A549 in vitro.
Inhibition of COX-2 blocked the release of IL-10 by LPS stimulated AM from smokers, may restore anti-tumor immunity.
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.
These findings support the continued investigation of COX-2 inhibitor in lung cancer chemoprevention.
II. Lung Cancer Chemoprevention II. Lung Cancer Chemoprevention with Celecoxib in Ex-Smokerswith Celecoxib in Ex-Smokers
Overall Objectives To determine the feasibility of Celecoxib for
chemoprevention of lung cancer in high risk ex-smokers. 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 II. Lung Cancer Chemoprevention with Celecoxib in Ex-Smokerswith Celecoxib in Ex-Smokers
Screening
Enrollment
Follow up
Former smokers, > 30 pk-yrs, age >45;
Stage I NSCLC post curative resection
Baseline risk assessment: 1. Questionnaires 2. Spirometry3. Sputum induction 4. LIFE Bronch5. Spiral CT 6. Buccal smear7. Blood 8. Urine collection.
Lung Cancer detected: ineligible
1:1 RandomizationStratification: 1. Prior stage I NSCLC.
2. preneoplasia
II. Lung Cancer Chemoprevention II. Lung Cancer Chemoprevention with Celecoxib in Ex-Smokerswith Celecoxib in Ex-Smokers
6 months placebo
6 months Celebrex
1:1 Randomization
Repeat LIFE bronch, buccal smear, blood,
urine and questionnaires at 6
mo.6 months placebo
6 months Celebrex
CROSSOVER
CROSSOVER
Repeat LIFE bronch, CT, buccal smear, blood,
urine and questionnaires at 12
mo.
RECRUITMENT FLOWCHARTRECRUITMENT FLOWCHART
In e lig ib le*2 ,099
In e lig ib le ****1 64
E n ro lled1 20
In P ro ce ss13
W a lk -In S c re en2 97
P e n d in g **52
D e c lin e d ***1 ,558
T o ta l N u m b e r o f In qu iries4 ,006
1. Bronchial biospsiesImmunostaining: Ki-67, COX-2, EGFR, p16, p27, cyclin D1 & E, bcl-2, p53, CD44,HistopathologyFrozen biopsy: CXC chemokines. RNA from homogenates.DNA analysis : GSTP1, p16 methylation. GSTP1, GSTM1, CYP1A1, P53 polymorphisims.
2. . BALFluid: PGE2, IL10, IL-12, VGEF, CXC chemokines, MMP, TIMP-1, LTB4CytologyAlveolar Macrophages: 1.Functional analysis. 2. RNA
3. Sputum: CytologyImmunostaining
4. BloodPlasma: PGE2Buffy coat
5. Buccal SmearDNA analysis
6. Urine
7. Primary Tumor:
Cox-2
Laboratory Studies and SEBM
Buccal Cell Genotyping Buccal Cell Genotyping
w ith o u tb ron ch
61
n o rm a l p a th onb ro n ch ia l b io p sy
41
S q ua m o usm e tap la s ia
33
T o ta l # sub je c ts w ithb a se lin e bu cca l ce ll a ssa yed
1 35
~ 137 SNP genotyping assays were performed using the Applied Biosystems SNPlex assay.
Buccal Cell genotypingBuccal 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. BailowR. Strieter F. BaratelliD. 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
PathologyM. Fishbein
J.Y. Rao
Oncology
R. Figlin
BiostatisticsR. ElashoffH-J. Wang
EpidemiologyZ-F. Zhang
C ChunW. CaoUCSD
K. Serio
SUPPORTSUPPORT
TRDRP CRFA NCI/K23 NCI/UO1 UCLA Lung Cancer SPORE Stop Cancer Miller Family Grant Study drugs from Pfizer, Inc.