|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 30 (October 20), 2006: pp. 4798-4800 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.0622
Did Targeted Therapy Fail Cyclooxygenase Too?Vanderbilt-Ingram Cancer Center, Division of Hematology and Oncology, Nashville, TN
There are considerable preclinical and clinical data showing that cyclooxygenase-2 (COX-2) plays an important role in the pathogenesis of non–small-cell lung cancers (NSCLC).1,2 COX-2 is one of two isoforms of COX that catalyzes the conversion of arachidonic acid to prostaglandin (PG) G2, which is then reduced to an unstable endoperoxide intermediate, PGH2.3 Specific PG synthases in turn metabolize PGH2 to at least five structurally related bioactive lipid molecules, including PGE2, PGD2, PGF2 Celecoxib has many potential molecular targets, including some that are COX-2-independent.6 However, the intended target in the Lilenbaum et al trial clearly was COX-2. Thus, at a minimum, it is critical to know two things: was COX-2 overexpressed in the treated tumors and did celecoxib inhibit intratumoral COX-2 activity? No such data are provided and, therefore, no definitive conclusion can be made regarding the efficacy of celecoxib in NSCLC based on the results of this trial. In fairness, it is extremely difficult to obtain adequate tumor samples to assess intratumoral COX-2 levels in recurrent NSCLC, and employing tissue from an earlier biopsy is hardly ideal as expression may change over time. However, this is not a trivial issue. Edelman and colleagues7 recently reported that celecoxib combined with chemotherapy appeared to improve survival in selected NSCLC patients in whom high expression of intratumoral COX-2 was identified (as assessed by immunohistochemical staining) compared with patients with high COX-2 expression who were given chemotherapy alone. These data are consistent with an earlier study that found celecoxib combined with preoperative chemotherapy appeared to improve response rates in NSCLC relative to chemotherapy alone.8 Accordingly, knowledge of the intratumoral COX-2 status might have provided considerable insight vis-à-vis the negative outcome of this trial. Of course, to favorably modulate a molecular target like COX-2, the drug must be delivered to the intended target. If we assume that the tumors of the patients enrolled in this trial overall had high COX-2 activity, it is quite possible that the negative findings are simply the result of inadequate celecoxib dosing. Indeed, recent work carried out by Reckamp et al9 indicate that maximum suppression of COX-2 activity, as assessed by changes in the level of the major urinary metabolite of PGE2 (PGE-M),10 requires a minimum daily celecoxib dose of at least 1,200 mg. This is a full one third higher than the dose used in the Lilenbaum et al study. Smoking status, also not commented on in this report, is an important determinant of COX-2 activity and endogenous PGE2 levels, as well. Active smokers typically have higher COX-2 activity than former smokers, who in turn have higher COX-2 activity than never smokers.11,12 In previous reports, a fixed dose of celecoxib inhibited PGE2 production to a greater degree in never and former smokers compared with current smokers.11,12 Not knowing the smoking status of the participants in the Lilenbaum trial makes interpretation of their data even more difficult. Notably, the choice of chemotherapy agents also may confound interpretation of this study, as taxanes have been shown to induce COX-2 in lung cancer cell lines by stimulating both transcription and mRNA stability leading to increase PGE2 production.13,14 The increase in PGE2 that in part may account for the myalgias observed in some patients after paclitaxel therapy might also reduce the potential beneficial effects of celecoxib—particularly if the dose of the selective COX-2 inhibitor is fixed, as was the case in the Lilenbaum et al trial. Is it possible that celecoxib contributed to a worse outcome, as suggested in one arm of this trial? Although COX-2 selective inhibitors suppress PGE2 production, the potential inhibition of endothelial cell derived COX-2 activity and subsequent PGI2 production may promote platelet aggregation and lead to an increased risk of coronary thrombosis and stroke.15 However, there is no indication that patients in this study fared less well because of cardiac toxicity. However, PGI2 also has been shown to suppress inflammation, prevent metastases, and inhibit the growth of micrometastases.16,17 Thus, a decrease in PGI2 levels could have an adverse effect on tumor growth particularly if PGE2 levels remained elevated or increased relative to PGI2 levels.16 How might this occur in the presence of selective COX-2 inhibition? The microsomal form of PGE synthase (mPGES), the tissue-specific enzyme that preferentially converts PGH2 to PGE2, is often upregulated in NSCLC.18 By contrast, 15-PG dehydrogenase (15-PGDH), the major enzyme responsible for PGE2 metabolism and elimination, is frequently downregulated in NSCLC.19,20 Thus, after selective COX-2 inhibition, PGE2 levels may remain elevated in NSCLC due to upregulation of mPGES or downregulation of 15-PGDH (or some combination of these events) while at the same time PGI2 levels decrease. This shift in the PGE2:PGI2 ratio may actually promote tumor growth rather than effect the desired growth inhibition (Fig 1). 16
What do these data tell us regarding the role of COX-2 inhibition in the management of recurrent NSCLC? The data are simply insufficient to allow us to definitively answer this question. Unfortunately, this trial joins a long list of missed opportunities to better characterize and understand the biology underlying our therapeutic failures as well as our therapeutic successes. Ideally, future studies employing COX-2 inhibitors will attempt to select patients with tumors more amenable to the potentially beneficial effects of a drug like celecoxib. At a minimum, this might include an assessment of COX-2 expression by immunohistochemistry as suggested by the work of Edelman et al.7 In addition, we and others have found that changes in urinary PGE-M levels also might be useful in this regard.9-12 A marked reduction in urinary PGE-M levels after a brief course of celecoxib seemingly predicts for a better outcome with continued COX-2 inhibition compared with those patients with little or no change in PGE-M levels.11 The immunohistochemistry and PGE-M data require confirmation, of course, but if validated the results suggest some lung cancers may be uniquely COX dependent and therefore more appropriate for inclusion in future studies employing COX inhibiting drugs. In addition, correlative studies are needed to assess the effectiveness of target acquisition and inhibition, such as measurement of the urinary metabolites of PGE2. It also may be possible to better characterize lung tumors at the molecular level and to use the data to direct the choice of COX inhibitor therapy. For example, if a particular tumor demonstrates overexpression of COX-2 and downregulation of 15-PGDH, indomethacin might be a good agent to consider as it blocks COX activity at a clinically tolerable dose and upregulates 15-PGDH expression through its PPAR  (peroxisome proliferator-activated receptors–gamma) agonistic property.20 Finally, because the activities of PGE2 are mediated by a family of G protein, coupled receptors linked to diverse intracellular signaling pathways,21 drugs that specifically target the receptors, rather than the upstream modulators, may circumvent some of the potential problems in assessing the role of COX inhibition we have explored. This approach has proved promising in preclinical studies.22,23 We believe continued efforts to modulate the arachidonic acid pathway are appropriate—the results of this trial notwithstanding. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Supported in part by National Institutes of Health Grants No. CA68485 and CA90949 (Lung Specialized Programs of Research Excellence) and by a grant from the Bristol-Myers Squibb Foundation for translational research in cancer. REFERENCES 1. Brown JR, DuBois RN: Cyclooxygenase as a target in lung cancer. Clin Cancer Res 10:4266s-4269s, 2004[CrossRef][Medline] 2. Krysan K, Reckamp KL, Sharma S, et al: The potential and rationale for COX-2 inhibitors in lung cancer. Anticancer Agents Med Chem 6:209-220, 2006[Medline] 3. Wang D, DuBois RN: Prostaglandins and cancer. Gut 55:115-122, 2006 4. Hida T, Kozaki K, Muramatsu H, et al: Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clin Cancer Res 6:2006-2011, 2000 5. Lilenbaum R, Socinski MA, Altorki NK, et al: A randomized phase II trial of docetaxel/irinotecan and gemcitabine/irinotecan with or without celecoxib in the second-line treatment of non–small cell lung cancer. J Clin Oncol 24:4825-4832, 2006 6. Grosch S, Maier TJ, Schiffmann S, et al: Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst 98:736-747, 2006 7. Edleman MJ, Watson DM, Wang X, et al: Eicosanoid modulation in advanced non-small cell lung cancer (NSCLC): CALGB 30203. J Clin Oncol 24:370s, 2006 (suppl; abstr 7025)[CrossRef] 8. Altorki NK, Keresztes RS, Port JL, et al: Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer. J Clin Oncol 21:2645-2650, 2003 9. Reckamp KL, Krysan K, Morrow JD, et al: A phase I trial to determine the optimal biological dose of celecoxib when combined with erlotinib in advanced non-small cell lung cancer. Clin Cancer Res 12:3381-3388, 2006 10. Murphey LJ, Williams MK, Sanchez SC, et al: Quantification of the major urinary metabolite of PGE(2) by a liquid chromatographic/mass spectrometric assay: Determination of cyclooxygenase-specific PGE(2) synthesis in healthy humans and those with lung cancer. Anal Biochem 334:266-275, 2004[CrossRef][Medline] 11. Csiki I, Morrow JD, Sandler A, et al: Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: A phase II trial of celecoxib and docetaxel. Clin Cancer Res 11:6634-6640, 2005 12. Gross ND, Boyle JO, Morrow JD, et al: Levels of prostaglandin E metabolite, the major urinary metabolite of prostaglandin E2, are increased in smokers. Clin Cancer Res 11:6087-6093, 2005 13. Subbaramaiah K, Hart JC, Norton L, et al: Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2: Evidence for involvement of ERK1/2 and p38 mitogen- activated protein kinase pathways. J Biol Chem 275:14838-14845, 2000 14. Subbaramaiah K, Marmo TP, Dixon DA, et al: Regulation of cyclooxgenase-2 mRNA stability by taxanes: Evidence for involvement of p38, MAPKAPK-2, and HuR. J Biol Chem 278:37637-37647, 2003 15. Mukherjee D, Nissen SE, Topol EJ: Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954-959, 2001 16. Nana-Sinkam P, Golpon H, Keith RL, et al: Prostacyclin in human non-small cell lung cancers. Chest 125:141S, 2004 (suppl 5) 17. Honn KV, Cicone B, Skoff A: Prostacyclin: A potent antimetastatic agent. Science 212:1270-1272, 1981 18. Yoshimatsu K, Altorki NK, Golijanin D, et al: Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer. Clin Cancer Res 7:2669-2674, 2001 19. Ding Y, Tong M, Liu S, et al: NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer. Carcinogenesis 26:65-72, 2005 20. Yang L, Kikuchi T, Amann J, et al: Inhibition of EGFR signaling elevates 15-hydroxyprostaglandin dehydrogenase in non-small cell lung cancer. Proc Am Assoc Cancer Res 47:20, 2006 (abstr 1343)[Medline] 21. Narumiya S, Sugimoto Y, Ushikubi F: Prostanoid receptors: Structures, properties, and functions. Physiol Rev 79:1193-1226, 1999 22. Ma X, Kundu N, Rifat S, et al: Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis. Cancer Res 66:2923-2927, 2006 23. Yang L, Huang YH, Porta R, et al: Profound reduction in tumor metastasis with selective EP4 receptor antagonism. Cancer Res (in press)
Related Correspondence
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
, PGI2, and thromboxane A2 (TxA2).
