© The Author 2006. Published by Oxford University Press.
EDITORIAL |
The Retinoic Acid Paradox in Cancer Chemoprevention
Affiliations of authors: Departments of Pharmacology and Toxicology (SJF, ED) and Medicine (KHD, ED), Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH; Dartmouth-Hitchcock Medical Center, Lebanon, NH (SJF, KHD, ED)
Correspondence to: Sarah J. Freemantle, PhD, Remsen 7650, Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755 (e-mail: sarah.freemantle{at}dartmouth.edu).
Decades of basic scientific studies and initial clinical trials have indicated a potential role for the classical retinoids in cancer chemoprevention (1). Indeed, the concept of clinical cancer chemoprevention is based largely on preclinical and early clinical studies in which retinoids suppressed epithelial carcinogenesis (2–5). However, in a recent randomized phase III intergroup chemoprevention trial, the retinoid isotretinoin did not reduce second primary tumor formation, recurrences, or mortality in patients with stage I non–small-cell lung cancer (6). And in this issue of the Journal, Khuri et al. (7) report results of a rigorously conducted placebo-controlled phase III trial showing that isotretinoin was not effective in mediating chemoprevention in patients with early-stage head and neck squamous cell carcinoma (HNSCC). It is now important to uncover the basis for this paradoxical lack of isotretinoin clinical chemoprevention activity. Answers will likely come from a more complete understanding of the molecular mechanisms and pharmacology of retinoids.
Retinoids comprise natural and synthetic derivatives of vitamin A that regulate many essential biologic functions. Retinoids activate transcription by binding to nuclear receptors. Isotretinoin, also known as 13-cis-retinoic acid, is converted to all-trans-retinoic acid, which activates the classical nuclear retinoic acid receptors (RARs), whereas 9-cis-retinoic acid activates both the RARs and the nonclassical nuclear retinoid X receptors (RXRs). RARs can heterodimerize with RXRs, whereas RXRs heterodimerize with other nuclear receptors, including the thyroid hormone receptor, the vitamin D receptor, and peroxisome proliferator–activated receptors (8). Novel synthetic retinoids, including RXR-selective agonists termed "rexinoids," have recently shown promising clinical activity in a combination regimen that targets non–small-cell lung cancer (9). Because RXRs form heterodimers with nuclear receptors that affect lipid physiology, their effects are also being investigated in other medical conditions, including the metabolic syndrome, which is characterized by obesity, dyslipidemia, diabetes, and hypercoagulability (8).
The retinoid-signaling pathway was studied in normal and neoplastic tissues to identify why preclinical retinoid activity did not readily translate into clinical success. It was discovered that expression of retinoic acid receptor 
(RAR) is frequently silenced in epithelial carcinogenesis, which has led to the hypothesis that RAR acts as a tumor suppressor that is partially responsible for the limited clinical activity of classical retinoids (10,11). Restoration of RAR expression in premalignant oral lesions by isotretinoin treatment was associated with a beneficial clinical response, implying a direct role for RAR as a mediator of retinoid response and as a biomarker for clinical chemoprevention (12). Clinical strategies to enhance retinoid activity include efforts to reduce toxicity, retain bioavailability, activate specific retinoid receptors, and develop effective combination regimens (1). For example, topical all-trans-retinoic acid (tretinoin) has shown clinical activity in cervical intraepithelial neoplasia, overcoming the systemic toxicity associated with oral retinoid administration (13). Other approaches include the use of nonclassical retinoids that have retinoid receptor–independent properties or that target RXRs that would bypass RAR repression (1).
The trial reported by Khuri et al. (7) is the largest retinoid chemoprevention study to date in patients with early-stage head and neck cancer. The lack of clinical efficacy in reducing incidence of second primary tumors reported by these investigators is consistent with the findings observed in other trials that used classical retinoids or carotenoids for lung cancer chemoprevention (6,14–16). The clinical benefit of finding an effective, yet tolerable, dosage of a cancer chemopreventive agent should not be underestimated. The dosage of isotretinoin that was used in this trial (30 mg/day) is much lower than that used in a previously reported positive randomized placebo-controlled study (50–100 mg/m2/day) (4). Most patients in that prior study required dose reductions, and more patients in the isotretinoin arm than in the placebo arm did not complete the 12-month course. Therefore, the dosage used in this trial is likely to be the highest dosage that can be tolerated in long-term treatment. In a multivariable analysis, Khuri et al. (7) found that current smokers had statistically significantly higher rates of second primary tumors and mortality than did former and never smokers. This finding confirms the benefit of smoking cessation on clinical outcomes for HNSCC patients.
It is not known whether the lack of isotretinoin activity in this trial was due to inherent tumor resistance or to unfavorable pharmacokinetics. Phase III chemoprevention trials designed to evaluate a treatment by using cancer incidence as an endpoint are costly and time-consuming but essential for definitive assessments of clinical efficacy. Sustained efforts will be required to optimize chemopreventive regimens. One challenge for the future will be to design clinically predictive and mechanistic trials with validated biomarker endpoints to verify drug activity before initiating large phase III trials. For example, when using a classical retinoid it may be necessary to treat only those patients who have an intact retinoic acid–signaling pathway. In a breast cancer chemoprevention trial of the nonclassical retinoid fenretinide, effects on surrogate biomarkers, including circulating insulin-like growth factor I (IGF-I) and mammographic density, are now being analyzed (17). It is interesting that serum levels of IGF-I and IGF-binding protein have also been reported to predict the risk of second primary tumors in patients with HNSCC (18). Another downstream marker of retinoid receptor activity is the loss of expression of the cell cycle regulator cyclin D1 (19). In a proof-of-principle trial, decreased cyclin D1 protein expression in buccal swabs was used as a biomarker for cellular response in patients with aerodigestive tract cancers treated with the rexinoid bexarotene and the epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib (9).
In summary, this definitive randomized placebo-controlled phase III HNSCC trial conducted by Khuri and colleagues revealed that low-dose isotretinoin was not effective in reducing the incidence of second primary tumors or in increasing overall disease-free survival (7). The chemopreventive activities of other classical and nonclassical retinoids and of combination regimens that include retinoids should still be evaluated. Promising treatments include the combination of a rexinoid with an epidermal growth factor receptor inhibitor (9) and a synthetic acyclic retinoid that shows activity in preventing second primary hepatocellular carcinomas (20). We do not fully understand why classical retinoids that have shown promise in preclinical studies have not shown clinical activity in the chemoprevention of lung (6) and head and neck (7) cancers. Loss of RAR isoforms in epithelial carcinogenesis undoubtedly plays a role (10,11). Proof-of-principle trials are attractive for testing retinoid monotherapy and combination therapy to establish clinical pharmacologic activity. What is also evident is that retinoids are useful tools for identifying critical target genes and pathways that can reduce carcinogenesis (21). Through these ongoing studies, we might even resolve the nature of the retinoic acid paradox in cancer chemoprevention.
REFERENCES
(1) Freemantle SJ, Spinella MJ, Dmitrovsky E. Retinoids in cancer therapy and chemoprevention: promise meets resistance. Oncogene 2003;22:7305–15.[CrossRef][Web of Science][Medline]
(2) Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 1976;35:1332–8.[Web of Science][Medline]
(3) Hong WK, Endicott J, Itri LM, Doos W, Batsakis JG, Bell R, et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986;315:1501–5.[Abstract]
(4) Hong WK, Lippman SM, Itri LM, Karp DD, Lee JS, Byers RM, et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990;323:795–801.[Abstract]
(5) Pastorino U, Infante M, Maioli M, Chiesa G, Buyse M, Firket P, et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 1993;11:1216–22.
(6) Lippman SM, Lee JJ, Karp DD, Vokes EE, Benner SE, Goodman GE, et al. Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 2001;93:605–18.
(7) Khuri FR, Lee JJ, Lippman SM, Kim ES, Cooper JS, Benner SE, et al. Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients. J Natl Cancer Inst 2006;98:441–50.
(8) Shulman AI, Mangelsdorf DJ. Retinoid x receptor heterodimers in the metabolic syndrome. N Engl J Med 2005;353:604–15.
(9) Dragnev KH, Petty WJ, Shah S, Biddle A, Desai NB, Memoli V, et al. Bexarotene and erlotinib for aerodigestive tract cancer. J Clin Oncol 2005;23:8757–64.
(10) Petty WJ, Li N, Biddle A, Bounds R, Nitkin C, Ma Y, et al. A novel retinoic acid receptor beta isoform and retinoid resistance in lung carcinogenesis. J Natl Cancer Inst 2005;97:1645–51.
(11) Xu XC, Ro JY, Lee JS, Shin DM, Hong WK, Lotan R. Differential expression of nuclear retinoid receptors in normal, premalignant, and malignant head and neck tissues. Cancer Res 1994;54:3580–7.
(12) Lotan R, Xu XC, Lippman SM, Ro JY, Lee JS, Lee JJ, et al. Suppression of retinoic acid receptor-beta in premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med 1995;332:1405–10.
(13) Abu J, Batuwangala M, Herbert K, Symonds P. Retinoic acid and retinoid receptors: potential chemopreventive and therapeutic role in cervical cancer. Lancet Oncol 2005;6:712–20.[CrossRef][Web of Science][Medline]
(14) The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029–35.
(15) Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145–9.
(16) Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150–5.
(17) Decensi A, Veronesi U, Miceli R, Johansson H, Mariani L, Camerini T, et al. Relationships between plasma insulin-like growth factor-I and insulin-like growth factor binding protein-3 and second breast cancer risk in a prevention trial of fenretinide. Clin Cancer Res 2003;9:4722–9.
(18) Wu X, Zhao H, Do KA, Johnson MM, Dong Q, Hong WK, et al. Serum levels of insulin growth factor (IGF-I) and IGF-binding protein predict risk of second primary tumors in patients with head and neck cancer. Clin Cancer Res 2004;10:3988–95.[CrossRef][Medline]
(19) Dragnev KH, Pitha-Rowe I, Ma Y, Petty WJ, Sekula D, Murphy B, et al. Specific chemopreventive agents trigger proteasomal degradation of G1 cyclins: implications for combination therapy. Clin Cancer Res 2004;10:2570–7.
(20) Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 1996;334:1561–7.
(21) Pitha-Rowe I, Petty WJ, Feng Q, Koza-Taylor PH, Dimattia DA, Pinder L, et al. Microarray analyses uncover UBE1L as a candidate target gene for lung cancer chemoprevention. Cancer Res 2004;64:8109–15.
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