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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 825-827 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.9583
Novel Strategies for the Treatment of Lung Cancer: Modulation of EicosanoidsDepartments of Medicine and Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN Given that lung cancer remains the leading cause of cancer-related death in the United States,1 one might question the value of the last three decades of basic and clinical research in this disease. Indeed, although modern platinum-based chemotherapy regimens can double the median survival of non–small-cell lung cancer (NSCLC) patients diagnosed with advanced disease, few patients survive beyond 2 years, and curative therapy remains elusive.2 In fact, one might further assert that most of the survival improvement beyond that achieved with supportive care alone was realized almost 20 years ago with the introduction of cisplatin into standard care, and that little has changed since that time.3,4 Fortunately, the pace of therapeutic progress appears to be accelerating, driven in large part by our improved (and improving) knowledge of lung cancer biology.5 This knowledge has led to the initiation of seminal studies employing so-called targeted therapy that have yielded clear survival benefits in patients with advanced NSCLC.6,7
Encouraged by the aforementioned successes, investigators continue to focus on exploiting key molecular targets that have the potential to enhance therapeutic outcome.5 One area of particular interest involves the eicosanoids—prostaglandins (PG), prostacyclins, thromboxanes (Tx), and leukotrienes (LT)—which are signaling molecules generated through the oxygenation of arachidonic acid.8-10 They exert complex control over many bodily systems, mainly in inflammation or immunity, and act as messengers in the CNS. Recently, a number of preclinical, clinical, and pharmacologic studies have documented the importance of eicosanoids in the development of many cancers, including NSCLC.8-10 For example, cyclooxygenase-2 (COX-2), one of two isoforms of COX that catalyzes the conversion of arachidonic acid to prostaglandin PGG2, is frequently upregulated in NSCLC.8,9 PGG2 is subsequently reduced to PGH2, an unstable endoperoxide intermediate. Specific PG synthases metabolize PGH2 to at least five structurally related bioactive lipid molecules: PGE2, PGD2, PGF2
In this issue of the Journal of Clinical Oncology, Edelman et al11 report the results of Cancer and Leukemia Group B (CALGB) trial 30203 in which patients with advanced NSCLC were randomly assigned to receive a standard platinum-based chemotherapy plus celecoxib (a specific COX-2 inhibitor) or chemotherapy with zileuton (a 5-lipoxygenase [LOX] inhibitor), or chemotherapy with both celecoxib and zileuton. LOX is a key enzyme in the production of LT known to increase cellular proliferation, increase transcriptional activity of oncogenes, and decrease apoptosis.12 The overall results of this randomized phase II trial were not particularly encouraging as none of the treatment regimens increased overall survival compared with historical controls treated with chemotherapy alone. Consistent with previous reports,13 however, patients with tumors that expressed moderate to high COX-2 levels as assessed by immunohistochemistry had a poor prognosis. Moreover, treatment with chemotherapy plus celecoxib effected a superior survival in patients with high intratumoral COX-2 expression compared with their counterparts treated with chemotherapy alone. This finding is consistent with a recent report by Chan et al, who noted that regular aspirin use reduced the risk of colorectal cancers that overexpress COX-2 but not the risk of colorectal cancers with weak or absent expression of COX-2.14 These data collectively suggest that cancers expressing high COX-2 levels may be "addicted" to COX-2 enzymatic activity and therefore potentially more susceptible to COX-2 inhibitors.15 This is an eminently testable hypothesis. For example, patients with high intratumoral COX-2 levels might be randomly assigned to receive chemotherapy plus a COX-specific inhibitor or a placebo. Another option might be to select patients using a biomarker of intratumoral COX-2 because adequate tumor samples are not always readily available in lung cancer patients. To this end, we recently developed an assay to measure urinary 11 In addition to upregulation of COX-2,18,19 there is mounting evidence that several COX-2–independent genes involved in eicosanoid biosynthesis and signal transduction also might be viable drug targets for in lung cancer. For example, high expression of the microsomal form of PGE synthase (mPGES),20 the tissue-specific enzyme that preferentially converts PGH2 to PGE2, and downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH),21,22 which catalyzes the rate-limiting step of prostaglandin catabolism through enzymatic inactivation of PGE2, are alterations in the eicosanoid pathway frequently observed in NSCLC. Individually or collectively, these factors could lead to high or sustained levels of PGE2 and downstream signaling events that promote the development and growth of NSCLC.8-10 Drugs targeting these specific molecules or the specific receptors (EP1-4) through which PGE2 exerts its cellular effects could prove beneficial, but without the cardiovascular adverse effects observed with specific COX-2 inhibitors.23,24 Parenthetically, a potential benefit of targeting the biosynthetic and signaling pathways downstream of COX-2 is the availability of existing US Food and Drug Administration–approved drugs readily available for clinical testing. For example, erlotinib can increase the level of the PGE2 catabolic enzyme 15-PGDH in colorectal and selected lung cancer cell lines22,25; this observation may help explain why some lung cancers treated with erlotinib experience disease stabilization in the absence of an epidermal growth factor–activating mutation. Additionally, a recent retrospective study examining cancer rates among diabetics treated with thiazolidinediones (TZDs) found that lung cancer incidence rates were significantly lowered in TZD-treated compared with nontreated patients.26 The benefit derived from TZDs in this study could possibly be a result of off-target effects because both pioglitazone and rosiglitazone can reduce PGE2 levels by upregulating 15-PGDH expression in a peroxisome proliferator–activated receptor gamma-independent manner.27 In summary, the results of CALGB 30203 support the hypothesis that some NSCLCs are "addicted" to COX-2 enzymatic activity and strongly suggest that further studies are warranted. The data presented by Edelman et al support the need for a prospective study in which patients with advanced lung cancer are selected on the basis of COX-2 expression. Patients with high intratumoral COX-2 levels should be randomly assigned to receive a COX-specific inhibitor or placebo in combination with established chemotherapy regimens. We believe that the testing of COX-2-independent approaches, which offer a potentially lower risk of adverse cardiovascular effects, is warranted as well. The results of CALGB 30203 emphasize the need for additional studies examining eicosanoid modulation so that clinicians can determine more conclusively whether inhibition of this pathway can significantly improve overall survival of patients with NSCLC. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: David H. Johnson, Merck (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Manuscript writing: Michael G. Backlund, Joseph M. Amann, David H. Johnson Final approval of manuscript: Michael G. Backlund, Joseph M. Amann, David H. Johnson ACKNOWLEDGMENTS Supported in part by National Institutes of Health Grants No. CA68485 and CA90949 (Lung Specialized Programs of Research Excellence; D.H.J) and F32C130562 (M.G.B.). REFERENCES
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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