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Chemopreventive strategies against lung cancer recurrence

Institution: University of California, Los Angeles
Investigator(s): Jenny Mao, M.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9IT-0023 Award: $75,000
Subject Area: Cancer
Award Type: Inno Dev & Exp Awards (IDEAS)
Abstracts

Initial Award Abstract
Lung cancer is the leading cause of cancer death in this country. One of the major obstacles in treating lung cancer is its late presentation, when the options for treatment are primarily to relieve symptoms. The lack of effective therapy underscores the urgency to reevaluate current management strategies. With recent advances in diagnostic technology and our understanding of cancer biology, it is time to explore new frontiers of treatment such as chemoprevention – the use of a substance to prevent the development of cancer. Lung cancer arises through a complex interaction between an individual’s genetic susceptibility and environmental influences such as tobacco smoking. Smoking, the number one cause of lung cancer, produces injuries throughout the lung. Unfortunately, many of the injuries persist even after smoking cessation. In other words, ex-smokers remain at risk of developing lung cancer. This realization provides the driving force to the field of lung cancer chemoprevention. Previous research has shown that patients who have had successful surgery for their lung cancer have a high risk of developing secondary lung cancers; however, there are no specific interventions to combat this problem. The high accumulative cancer risk makes these patients ideal candidates for studying chemoprevention. The purpose of this project is, therefore, to evaluate a cyclooxygenase (Cox)-2 inhibitor, Celebrex (Celecoxib), for chemoprevention of secondary lung cancer.

The hypothesis to be tested in this proposal, that Celebrex can prevent the development of secondary lung cancers, is based on numerous laboratory data showing Celebrex’s ability to prevent or inhibit the growth of lung cancer cells in test tubes and in rats. Celebrex inhibits Cox-2, an enzyme that catalyze the formation of prostaglandin E2 (PGE2). PGE2 is a substance that plays important regulatory roles in a variety of physiologic functions. While a certain level of PGE2 is essential to maintain normal biologic functions in the body, excessive amounts have been shown to facilitate cancer development. There are two cyclooxygenases that catalyze the formation of PGE2. Cox-1 is primarily responsible for producing the maintenance level of PGE2, whereas Cox-2 is involved in the excess formation of PGE2. The simultaneous inhibition of Cox-1 and Cox-2 interferes with the maintenance functions of Cox-1, and thereby increases the risk of serious side effects, such as peptic ulcer disease. This problem may be avoided by selective inhibition of Cox-2. Celebrex has been approved by the FDA for treatment of arthritis. It causes few side effects and is safer than aspirin and ibuprofen. Its favorable safety profile adds to its potential as a chemopreventive agent.

In this study, we will (1) evaluate the ability of Celebrex for preventing secondary lung cancer or cancer recurrence; (2) determine if the production of Cox-2 in the lung cancer tissue affects patient’s response to Celebrex; and (3) validate PGE2, EGFR and Ki- 67 (special molecular markers) as surrogate indexes of chemopreventive response to Celebrex. To achieve these objectives, 40 individuals with a history of stage I non-small cell lung cancer (NSCLC), who have had successful surgeries will be recruited. All subjects will be screened for presence of lung cancer with fluorescence (LIFE) bronchoscopy and CT scan. Only patients who are free of active cancer will be enrolled. Subjects will be randomized in a double blind fashion, to receive either placebo or a Cox-2 inhibitor-oral celecoxib as a chemopreventive agent. All patients will be treated for 6 months, at which time they will undergo follow up LIFE bronchoscopy to assess the aforementioned surrogate endpoints. Moreover, serial tissue and serum specimen, respiratory and health questionnaires will be archived for future analysis. The finding from this pilot project will provide important insight into the design and conduct of future chemopreventive trials. If successful, the information gained from this study will set the stage for larger, more definitive trials. The potential gain for the management of lung cancer, for the study subjects, lung cancer survivors and people at risk of lung cancer in general, is enormous.
Publications

Celecoxib modulates the capacity for PGE2 and IL-10 production in alveolar macrophages from active smokers.
Periodical: Clinical Cancer Research Index Medicus:
Authors: Mao JT, Roth MD, Serio KJ, Baratelli LZ, Holmes EC, Strieter RM, Dubinett SM ART
Yr: 0 Vol: Nbr: Abs: Pg:

Surveillance and chemoprevention of second lung cancer.
Periodical: Southern California Pulmonary & Critical Care Research Conference Abstracts Index Medicus:
Authors: Mao JT, Roth MD, Holmes EC, Aberle D, Fishbein M, Dubinett SM ABS
Yr: 2001 Vol: Nbr: Abs: Pg:

Cox-2 inhibition modulates PGE2 and IL-10 production in human alveolar macrophages from active smokers.
Periodical: ATS/Respiratory and Critial Care Medicine Index Medicus:
Authors: Mao JT, Zhu L, Baratelli F, Roth MD, Tashkin DP, Holmes EC, Dubinett SM ABS
Yr: 2002 Vol: Nbr: Abs: Pg:

Feasibility of celecoxib in lung cancer chemoprevention in active smokers.
Periodical: ATS/Respiratory and Critial Care Medicine Index Medicus:
Authors: Mao JT, Zhu L, Baratelli F, Roth MD, et al. ABS
Yr: 2003 Vol: Nbr: Abs: Pg: