|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 4865-4867 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.1060
Thinking In and Out of the Box When It Comes to Gastric Cancer and Cyclooxygenase-2Departments of Experimental Therapeutics and Gastrointestinal Medical Oncology, the University of Texas M.D. Anderson Cancer Center, Houston, TX Prostaglandin G/H synthetase or cyclooxygenase (COX) was discovered in the 1970s, when it was noted that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibited its proinflammatory activity.1 Subsequent studies in humans revealed that COX-2, one of the two COX isoforms, participated in colon cancer progression (familial adenomatous polyposis [FAP], Gardner's syndrome, and sporadic colon cancer) and that its inhibition by the NSAIDs could have a preventive effect.2-6 These studies generated a great deal of scientific and commercial enthusiasm culminating in the approval of celecoxib in 1999 by the US Food and Drug Administration for the prevention of colorectal polyps in patients with FAP.7,8 COX-2 is the key in the metabolism of arachidonic acid and it catabolizes the biosynthesis of five function-specific prostaglandins (PG) including PGE2, PGD2, PGF2a, PGI2, and thromboxane.9 As opposed to COX-1, which is physiologically constitutively expressed in a variety of tissues, COX-2 expression is absent under normal conditions but its expression is rapid in response to proinflammatory cytokines and certain hormones.9 COX-2 expression is aberrantly upregulated in a wide variety of human preneoplastic and neoplastic (breast, gastrointestinal, bladder, lung, and prostate) conditions.10 COX-2 overexpression can lead to the production of PGE2 and to a lesser extent thromboxane, both implicated in angiogenesis, cell proliferation, cell survival, migration, invasion, and modulation of host immune cells.11 Importantly, COX-2–derived PGE2 can cross-talk with other molecular pathways important for cancer progression (Fig 1). 11 An example would be the activation of the epidermal growth factor receptor pathway responsible for increased cell motility, invasion, and metastases (Fig 1).12
Since 1992, there have been approximately 10,962 COX-2–related publications and many studies of human cancer have associated its overexpression with poor patient outcome as well as with large tumor size and lymph node and distant metastases. In this issue of the Journal, de Maat et al13 report on COX-2 in gastric cancer by adopting a novel approach to judge the impact of "underexpression or lack of expression" on patient outcome. To our knowledge, this study may be the first to correlate the absence of COX-2 expression and hypermethylation of the COX-2 promoter with the conclusion that the hypermethylated status is associated with a better clinical outcome (this conclusion, however, is an anticipated one and not novel). DNA methylation—the addition of a methyl group to one of the four DNA bases14—is important for maintenance of chromatin structure and sustained suppression of gene expression (ie, epigenetic silencing). In cancer, the epigenetic silencing is deregulated as a result of global hypomethylation that is associated with chromosomal instability and inappropriate methylation of gene promoters, often tumor suppressor genes (ie, the gatekeeper genes).15 The loss of function of tumor suppressor genes during cancer development/progression is a consequence of promoter hypermethylation, loss of heterozygosity, and gene mutations. The fact that the COX-2 protein expression persists even when the methylation indices are high suggests that other genetic (eg, COX-2 promoter polymorphism) or epigenetic factors (eg, the type, number, and/or overexpression of transcription factors stimulating COX-2 expression) might be participating. Unraveling these issues would have increased our understanding of gastric cancer and COX-2 biology. In addition, the genome-wide assessment of methylated and expressed genes could further improve our knowledge about the other genes that probably coparticipate in defining various phenotypes.16 Gastric cancer is a worldwide health burden of a monumental proportions.17 The progress against gastric cancer has been painfully slow. Even after a curative resection (R0) alone or after adjuvant therapy, nearly 60% of those patients affected succumb to gastric cancer.18,19 We have no tools to address the inherent molecular heterogeneity of gastric cancer that expresses itself in divergent clinical biology. As exemplified by de Maat et al, when using an empiric approach (surgery in this instance), the outcomes are unpredictable. We need validated biomarkers to individualize therapy for our patients. Accomplishing this remains a enormous task but the biotechnology is here to help us sort out the subgroups of gastric cancers (these exist even within a defined stage). It would require a complex model that incorporates cancer biology and patient genetics. To identify one discriminating biomarker (eg, COX-2 or p53) would be thinking within the box. It has not led to a new clinical algorithm. What if we knew that our next patient's T3N1 gastric cancer (after primary surgery) has a hypermethylated COX-2 promoter region? Are we not recommending postoperative chemoradiotherapy? Are we following such a patient much less frequently than others? Are we telling the patient that the chance of cure is higher because of this test? No, we do not, because a single biomarker is likely insufficient for making such clinical decisions or providing information. Cancer cells employ multiple and diverse survival pathways20 and it would be necessary to define a battery of biomarkers (complex signatures that define multiple outcomes). Such signatures might more appropriately represent the breadth of molecular diversity inherent in cancers in general, and gastric cancer is no exception. What could constitute thinking outside the box? Bild et al21 have suggested that the DNA microarray data can allow one to subtype cancers by identifying the type of activated pathways. This approach is of considerable appeal because constructing pathway-based signatures may allow us to classify cancers irrespective of their site of origin. Gastric cancers may have several subtypes based on the pathways being employed and some of these subtypes might be identical to subtypes of lung or other cancers. This could reduce the disadvantage gastric cancer patients have today (very few phase III trials compared with more common Western cancers). We can envision that a drug developed for a subgroup of breast or lung cancers (effective because a specific pathway signature is found) might be just as effective against a subset of gastric cancers that have the same pathway signature. This could eliminate the laborious clinical trials that we undertake today in individual tumor types. This approach would create an entirely new paradigm for drug development. Similarly, the molecular signatures will not only predict response to therapy but also patient prognosis. Such signatures (and their complexity is yet to be determined because they might include some or all of the omics and patient genetics) will individualize therapy and reduce today's rampant empiricism. We can envision that individualization of therapy based on molecular signatures would actually reduce the cost of oncology health care and clinical trials. Only patients who have a specific signature will receive a specific therapy and a clinical trial's eligibility might require the presence of a specific signature. This could increase the chance of obtaining maximum benefit from a drug (or combination) and reduce the costs that we incur today by treating many patients who do not benefit (but nearly all patients suffer from adverse effects). Furthermore, a patient's genetic data might allow us avoid potentially severely toxic therapies even when the other biologic parameters might suggest that if is likely to be efficacious against cancer. The possibilities are innumerable; however, we have only de Maat et al to thank for increasing our awareness of the next set of challenges facing us. Nevertheless, these are exciting times in oncology research. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Julie G. Izzo, Jaffer A. Ajani Administrative support: Jaffer A. Ajani Manuscript writing: Julie G. Izzo, Jaffer A. Ajani Final approval of manuscript: Jaffer A. Ajani
REFERENCES 1. Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 231 : 232 -235, 1971[Medline] 2. Pollard M, Luckert PH, Schmidt MA: The suppressive effect of piroxicam on autochthonous intestinal tumors in the rat. Cancer Lett 21 : 57 -61, 1983[CrossRef][Medline] 3. Waddell WR, Loughry RW: Sulindac for polyposis of the colon. J Surg Oncol 24 : 83 -87, 1983[Medline] 4. Waddell WR, Ganser GF, Cerise EJ, et al: Sulindac for polyposis of the colon. Am J Surg 157 : 175 -179, 1989[CrossRef][Medline] 5. Eberhart CE, Coffey RJ, Radhika A, et al: Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107 : 1183 -1188, 1994[Medline] 6. Thun MJ, Namboodiri MM, Heath CW Jr: Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325 : 1593 -1596, 1991[Abstract] 7. Steinbach G, Lynch PM, Phillips RK, et al: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342
: 1946
-1952, 2000 8. Arber N, Eagle CJ, Spicak J, et al: Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 355
: 885
-895, 2006 9. DuBois RN, Abramson SB, Crofford L, et al: Cyclooxygenase in biology and disease. FASEB J 12
: 1063
-1073, 1998 10. Cha YI, DuBois RN: NSAIDs and cancer prevention: Targets downstream of COX-2. Annu Rev Med 58 : 239 -252, 2007[CrossRef][Medline] 11. Wang D, DuBois RN: Prostaglandins and cancer. Gut 55
: 115
-122, 2006 12. Pai R, Soreghan B, Szabo IL, et al: Prostaglandin E2 transactivates EGF receptor: A novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 8 : 289 -293, 2002[CrossRef][Medline] 13. de Maat MFG, van de Velde CJH, Umetani N, et al: Epigenetic silencing of cyclooxygenase-2 affects clinical outcome in gastric cancer. J Clin Oncol 25
: 4887
-4894, 2007 14. Robertson KD: DNA methylation and human disease. Nat Rev Genet 6 : 597 -610, 2005[CrossRef][Medline] 15. Baylin SB, Herman JG, Graff JR, et al: Alterations in DNA methylation: A fundamental aspect of neoplasia. Adv Cancer Res 72 : 141 -196, 1998[Medline] 16. Esteller M: Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8 : 286 -298, 2007[CrossRef][Medline] 17. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 57
: 43
-66, 2007 18. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345
: 725
-730, 2001 19. Bonenkamp JJ, Hermans J, Sasako M, et al: Extended lymph-node dissection for gastric cancer. N Engl J Med 340
: 908
-914, 1999 20. Hahn WC, Weinberg RA: Modelling the molecular circuitry of cancer. Nat Rev Cancer 2 : 331 -341, 2002[CrossRef][Medline] 21. Bild AH, Potti A, Nevins JR: Linking oncogenic pathways with therapeutic opportunities. Nat Rev Cancer 6 : 735 -741, 2006[CrossRef][Medline] Related Article
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
