New paradigms for cancer prevention.

Raymond N.DuBois antibody targeted for the Her-2/neu receptor. However, a role for EGFR-kinase inhibitors in cancer prevention was previously Departments of Medicine and Cell Biology, Vanderbilt University Medical noted because the EGFR signaling pathway was known to be Center, The Vanderbilt-Ingram Cancer Center, Nashville, TN 37232-2279, dysregulated in many different types of cancer, including USA carcinomas of the colon, breast and lung (14). The precise To whom correspondence should be addressed role of the EGFR in neoplastic transformation continues to be Email: raymond.dubois@mcmail.vanderbilt.edu an area of intense investigation. Obviously, activation of the EGFR-associated tyrosine kinase activity stimulates multiple Non-steroidal anti-inflammatory drugs (NSAIDs) have been signaling pathways, which culminates in increased cell divistudied extensively for their ability to delay or inhibit the sion, altered cell motility and a number of other biologic development of malignant and pre-malignant lesions (1). There responses. EGFR activation also leads to increased expression has been a considerable amount of attention focused on this of the cyclooxygenase-2 (COX-2) gene (15). Several groups class of drugs because of previous clinical and epidemiologic have shown a role for COX-2 in carcinogenesis (16–21). The studies indicating that they possess anti-neoplastic activity. cyclooxygenase pathway may have particular significance Clinical observations by Waddell and Loughry first indicated because the activity of this enzyme is inhibited by NSAIDs. that use of these agents led to regression of adenomas in Therefore, inhibition of EGFR-associated tyrosine kinase patients with Familial Adenomatous Polyposis (FAP) (2). Ten activity affects a number of signaling pathways, including the years later, clinical trials confirmed a significant reduction in induction of cyclooxygenase expression. Addition of an NSAID the size and number of adenomas in FAP patients treated with inhibits the remaining cyclooxygenase activity in addition to sulindac (3). Since Waddell’s first clinical observation, a its effect on apoptosis and PPARδ (22). It will be important number of studies have been completed in a variety of animal to determine the cancer preventive effect of a combination of and laboratory models confirming an anti-neoplastic effect of COX-2 selective inhibitors plus EGFR-kinase inhibitors. Since NSAIDs (4). However, it is clear from all of the studies COX-2 selective NSAIDs have an improved gastrointestinal published to date that use of NSAIDs alone does not eradicate safety profile (23,24) these drugs may be better tolerated in all tumors. NSAIDs are known to inhibit the activity of humans. Therefore, the effectiveness of targeting multiple cyclooxygenase enzymes (5) and other pathways (6,7) that are signaling pathways in a systematic way is required to determine known to promote neoplastic transformation of cells. For effective prevention of colorectal cancer, complete the most effective combination of agents for cancer prevention. elimination of all adenomas is the desirable outcome. Since the use of one agent alone does not completely eliminate References premalignant disease, combinations of different agents for cancer prevention may be more effective. Several reports have 1.Smalley,W. and DuBois,R.N. (1997) Colorectal cancer and non steroidal anti-inflammatory drugs. Adv. Pharmacol., 39, 1–20. been published demonstrating that the combination of an 2.Waddell,W.R. and Loughry,R.W. (1983) Sulindac for polyposis of the NSAID plus difluoromethylornithine is much more effective colon. J. Surg. Oncol., 24, 83–87. than using either single agent alone (8–10). Importantly, there 3.Giardiello,F.M., Hamilton,S.R., Krush,A.J., Piantadosi,S., Hylind,L.M., appears to be less toxicity associated with this combination of Celano,P., Booker,S.V., Robinson,C.R. and Offerhaus,G.J. (1993) agents because lower dosages of each agent can be given to Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N. Engl. J. Med., 328, 1313–1316. obtain the same or better effect. Based on these findings, one 4.Giardiello,F.M., Offerhaus,G.J.A. and DuBois,R.N. (1995) The role of would predict that the use of combinations of chemopreventive nonsteroidal antiinflammatory drugs in colorectal cancer prevention. Eur. agents would be more effective. J. Cancer, 31A, 1071–1076. A recent report by Torrance et al. (11) indicates that 5.Williams,C.S., Mann,M. and DuBois,R.N. (1999) The role of treatment with an NSAID plus an epidermal growth factor cyclooxygenases in inflammation, cancer and development. Oncogene, 18, 7908–7916. receptor (EGFR)-kinase inhibitor leads to a significant reduc6.Lim,J.T., Piazza,G.A., Han,E.K. et al. (1999) Sulindac derivatives inhibit tion in polyp number in the Min mouse model. The results growth and induce apoptosis in human prostate cancer cell lines. Biochem. are dramatic, with polyp incidence in Min mice being reduced Pharmacol., 58, 1097–1107. by 95% using the co-administration of sulindac and EKB7.Wu,G.D. (2000) A nuclear receptor to prevent colon cancer. New Engl. J. 569. Surprisingly, nearly half of the animals in the treated Med., 342, 651–653. 8. Jacoby,R.F., Cole,C.E., Tutsch,K., Newton,M.A., Kelloff,G., Hawk,E.T. group did not develop any discernible polyps over the duration and Lubet,R.A. (2000) Chemopreventive efficacy of combined piroxicam of the study. Since Stanley Cohen’s initial discovery of the and difluoromethylornithine treatment of Apc mutant Min mouse adenomas EGF 40 years ago (12), it was predicted that a therapeutic and selective toxicity against Apc mutant embryos. Cancer Res., 60, target for cancer would emerge from a better understanding 1864–1870. of this signaling pathway (13). The first drug approved for 9.Li,H., Schut,H., Conran,P., Kramer,P., Lubet,R., Steele,V., Hawk,E., Kelloff,G. and Pereira,M. (1999) Prevention by aspirin and its combination cancer therapy from this general signaling pathway was an with alpha-difluoromethylornithine of azoxymethane-induced tumors, aberrant crypt foci and prostaglandin E2 levels in rat colon. Carcinogenesis, Abbreviations: COX-2, cyclooxygenase-2; EGFR, epidermal growth factor receptor; NSAIDS, non-steroidal anti-inflammatory drugs. 20, 425–430.