Novel Strategies for the Treatment of Lung Cancer: Modulation of Eicosanoids

Abstract

Given that lung cancer remains the leading cause of cancerrelated death in the United States, 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. 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. Fortunately, the pace of therapeutic progress appears to be accelerating, driven in large part by our improved (and improving) knowledge of lung cancer biology. 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. Encouraged by the aforementioned successes, investigators continue to focus on exploiting key molecular targets that have the potential to enhance therapeutic outcome. 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. 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. 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 , PGI2, and TxA2. 10 In turn, COX-2–derived PGE2 can stimulate cellular proliferation and angiogenesis, reduce apoptosis, enhance cellular invasiveness, and inhibit immune surveillance. Each of these contributes to the pathogenesis and progression of NSCLC. Strategies designed to decrease PGE2 production are therefore thought to represent possible therapeutic options in NSCLC. In this issue of the Journal of Clinical Oncology, Edelman et al 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. 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, 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. 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. 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 -hydroxy-9,15dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of PGE2. 16 We found that nonselective and selective inhibitors of COX-2 effectively decreased urinary PGE-M levels to a similar degree in healthy human participants and in individuals with NSCLC, indicating that a majority of PGE-M in humans, with or without an underlying malignancy, is COX-2 derived. We also found that a short course of moderately high-dose celecoxib (400 mg bid) resulted in a marked decrease in intratumoral PGE2 levels, with a concomitant decline in urinary PGE-M levels. Collectively, these data indicate that urinary PGE-M could be a useful biomarker of intratumoral COX-2 activity and PGE2 production in NSCLC. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 6 FEBRUARY 2