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UCLA Lung Cancer Chemoprevention Trials

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. Leading cause of cancer death in the world.

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UCLA Lung Cancer Chemoprevention Trials

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  1. 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

  2. Lung 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.

  3. 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.

  4. Lung Cancer Progression Model- Sequential Changes During Carcinogenesis Hirsch, F et al, 2001, Clin Cancer Res, 7:5-22

  5. 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.

  6. Growth factors Cytokines Carcinogens Inflammatory stimuli • Inflammatory Sites: • Mf • Endothelial • cells • Cancer TXA2 (inducible) COX-2 PGD2 AA PGE2 PGG2 PGH2 • Platelets • Stomach • Intestine • Kidney PGF2 COX-1 (constitutive) PGI2

  7. RATIONALE FOR COX-2 INHIBITION Tumor Invasiveness Celebrex Angiogenesis Apoptosis Premalignant lesions Cancer PGE2 Anti-tumor Immunity IL-10 IL-12

  8. I. Celecoxib for Chemoprevention of Primary 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.

  9. I. Celecoxib for Chemoprevention of Primary Lung Cancer Baseline Subject Characteristics Mean Range Age, yrs 54 47 - 7 Gender, M/F 9/11 - Smoking hx (pky) 42 20 -159 Ethnicity A/B/C/H 1/2/15/2 Family history 5 COPD 10/20

  10. I. Celecoxib for Chemoprevention of Primary Lung Cancer in Heavy Smoker • Outcome Measures • Modulation of Intra-pulmonary PGE2 production. • BAL cells functional analysis. Antitumor immunity: balance of IL-10 and IL-12 in the lung microenvironment. • III. SEBM: Ki-67 (cellular proliferation), Histopathology.

  11. RESULTS 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). Mao J, et al, Clin Cancer Res. 2003

  12. RESULTS Post-treatment BAL fluid and plasma abrogated PGE2 production by stimulated NSCLC cells (A549) Mao J, et al, Clin Cancer Res. 2003

  13. RESULTS Inhibition of COX-2 decreased the LPS-induced, up-regulation of IL-10 by BAL cells collected from smokers. IL-10 (ng/ml) Mao J, et al, Clin Cancer Res. 2003

  14. 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

  15. Ki-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.

  16. A * Level of Ki-67 correlated with smoking history P = 0.032 Mao J, et al, Clin Cancer Res. 2006

  17. 6 months of Celecoxib reduced Ki-67 LI by 35%. Baseline * Final Mao J, et al, Clin Cancer Res. 2006

  18. Summary from 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.

  19. 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 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.

  20. II. Lung Cancer Chemoprevention with 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. Spirometry 3. Sputum induction 4. LIFE Bronch 5. Spiral CT 6. Buccal smear 7. Blood 8. Urine collection. Lung Cancer detected: ineligible 1:1 Randomization Stratification: 1. Prior stage I NSCLC. 2. preneoplasia

  21. 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 questionnaires at 6 mo. CROSSOVER CROSSOVER 6 months placebo 6 months Celebrex Repeat LIFE bronch, CT, buccal smear, blood, urine and questionnaires at 12 mo.

  22. RECRUITMENT FLOWCHART

  23. Laboratory Studies and SEBM 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 • Urine • Primary Tumor: • Cox-2

  24. Buccal Cell Genotyping ~ 137 SNP genotyping assays were performed using the Applied Biosystems SNPlex assay.

  25. 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)

  26. Acknowledgement Thoracic Surgery E.C. Holmes R. Cameron S. Perez Division of Pulmonary & Critical Care S. DubinettB. 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 Pathology M. Fishbein J.Y. Rao Oncology R. Figlin Thoracic Imaging D. Aberle Biostatistics R. Elashoff H-J. Wang Epidemiology Z-F. Zhang C Chun W. Cao UCSD K. Serio

  27. SUPPORT • TRDRP • CRFA • NCI/K23 • NCI/UO1 • UCLA Lung Cancer SPORE • Stop Cancer Miller Family Grant • Study drugs from Pfizer, Inc.

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