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Current Role and Future Directions of the Retinoic Acid Pathway in Cancer Prevention and Treatment

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Current Role and Future Directions of the Retinoic Acid Pathway in Cancer Prevention and Treatment Published OnlineFirst January 15, 2013; DOI: 10.1158/1078-0432.CCR-12-3175 Clinical Cancer Molecular Pathways Research Molecular Pathways: Current Role and Future Directions of the Retinoic Acid Pathway in Cancer Prevention and Treatment Roisin M. Connolly, Nguyen K. Nguyen, and Saraswati Sukumar Abstract Retinoids and their naturally metabolized and synthetic products (e.g., all-trans retinoic acid, 13-cis retinoic acid, bexarotene) induce differentiation in various cell types. Retinoids exert their actions mainly through binding to the nuclear retinoic acid receptors (a, b, g), which are transcriptional and homeostatic regulators with functions that are often compromised early in neoplastic transformation. The retinoids have been investigated extensively for their use in cancer prevention and treatment. Success has been achieved with their use in the treatment of subtypes of leukemia harboring chromosomal translocations. Promising results have been observed in the breast cancer prevention setting, where fenretinide prevention trials have provided a strong rationale for further investigation in young women at high risk for breast cancer. Ongoing phase III randomized trials investigating retinoids in combination with chemotherapy in non–small cell lung cancer aim to definitively characterize the role of retinoids in this tumor type. The limited treatment success observed to date in the prevention and treatment of solid tumors may relate to the frequent epigenetic silencing of RARb. Robust evaluation of RARb and downstream genes may permit optimized use of retinoids in the solid tumor arena. Clin Cancer Res; 19(7); 1651–9. Ó2013 AACR. Background Retinoic acid and the retinoic acid receptor pathway Vitamin A is derived from animal and plant food Retinoic acids (RA) exert their functions through their sources and has critical functions in many aspects of specific receptors. The 2 distinct classes of receptors are human biology. Its natural derivatives and metabolized retinoic acid receptors (RAR) and retinoic X receptors products (retinoids) such as b-carotene, retinol, retinal, (RXR). Each class contains 3 different subtypes—a, b, and isotetrinoin, all-trans retinoic acid (ATRA), 9-cis retinoic g (6). ATRA and fenretinide can bind specifically to RARS, cis cis acid, and 13-cis retinoic acid have important roles in cell 13- RA and bexarotene only to RXRS, and 9- RA to RARS differentiation, growth, and apoptosis (1). Synthetic reti- or RXRS (refs. 1, 5; Table 1). The expression of these noids are also available and include bexarotene and receptors is regulated by the receptors themselves, other fenretinide. In clinical practice, retinoids have a wide nuclear receptors such as ERa, or by other subtypes in the range of dermatologic indications including for psoriasis, same family (5, 7). Upon the binding of ligands, RARs and acneiform, and keratinization disorders (2). Systemic RXRs form heterodimers and function as ligand-dependent retinoids are approved by the U.S. Food and Drug Admin- transcription factors to activate their downstream effectors by binding to the retinoic acid response elements (RARE) istration (FDA) for the treatment of cutaneous T-cell 0 lymphoma (3) and acute promyelocytic leukemia (APL; located in the 5 -region of RA downstream genes (5). The refs. 4, 5). However, the chemopreventive and therapeutic above model of RAR or RXR function via binding to RARE is effects of retinoids in solid tumors remain controversial. considered the RA classical or genomic pathway. Activation Therefore, an overview of the research to date and future of the classical pathway will trigger cell differentiation, cell directions in this area is the focus of this review. arrest, and eventual apoptosis (8). The function of RA and its receptors involves not only the classical pathway but also multiple other important path- ways. RAs have been shown to regulate NF-kB (9), IFN-g Authors' Affiliation: Breast Cancer Program, Sidney Kimmel Compre- (10), TGF-b (11), VEGF (12), mitogen-activated protein hensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MAPK Maryland kinase ( ; ref. 13), and chromatin remodeling (14). Furthermore, RARs and RXRs can form heterodimers with Corresponding Authors: Saraswati Sukumar and Roisin Connolly, Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 143, other types of receptors, including the estrogen receptor-a Baltimore, MD 21287. Phone: 410-614-2479; Fax: 410-614-4073; E-mail: (ERa; refs. 7, 15), AP-1 receptor (16), peroxisome prolif- [email protected]; and [email protected] erator-activated receptor (PPAR; ref. 17), liver X receptors doi: 10.1158/1078-0432.CCR-12-3175 (LXR; refs. 18, 19), and vitamin D receptor (VDR; Ó2013 American Association for Cancer Research. ref. 20; Fig. 1). When RARs/RXRs heterodimerize with these www.aacrjournals.org 1651 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2013 American Association for Cancer Research. 1652 Clin Cancer Res; 19(7) April 1, 2013 Connolly et al. Downloaded from Table 1. Select clinical trials evaluating retinoids in solid tumors Retinoid Other names Target Clinical trial setting Dose and schedule (ref.) Study outcome Biomarker evaluation ATRA Tretinoin RAR Advanced NSCLC 20 mg/m2/d commencing 1 wk RR (55.8% vs. 25.4%) and No significant association Phase II randomized pre-paclitaxel/cisplatin every median PFS (8.9 vs. 6 months) between RAR-b2 expression (n ¼ 107) 3 wk (50) favored the ATRA arm and response rate detected Published OnlineFirstJanuary15,2013;DOI:10.1158/1078-0432.CCR-12-3175 clincancerres.aacrjournals.org Phase III study pending (n ¼ 60) Metastatic breast cancer 45 mg/m2/d for 4 d Clinical benefit rate of 76.4% Phase II single arm (n ¼ 17) commencing 2 d preweekly Note that the majority of paclitaxel (PMID 20596747) patients had not received prior paclitaxel 13-cis RA Isotretinoin RXR Primary prevention: HþN Induction phase: high dose Induction phase (n ¼ 66): RR Roaccutane cancer (1.5 mg/kg) for 3 mo; 55%; maintenance phase Accutane maintenance phase: low dose (n ¼ 53): response or stable (0.5 mg/kg/d) vs. b-carotene disease 92% (n ¼ 22, (30 mg/d) for 9 mo (30) isotretinoin) vs. 45% (n ¼ 13, b-carotene) on September 29, 2021. © 2013American Association for Cancer Advanced solid tumors 1 mg/kg twice daily 3 wk Antitumor activity observed Research. Phase I (n ¼ 13) of 4 with MS-275 (69) and recommended phase II dose determined Metastatic breast cancer 1 mg/kg/d þ tamoxifen No significant difference in RR Phase II randomized (n ¼ 99) 20 mg/m2 vs. tamoxifen alone or overall survival between vs. tamoxifen þ IFN-a-2a the 3 arms 3 MU 3 times weekly IM (62) 9-cis RA Alitretinoin RAR Metastatic breast cancer 70 mg/m2/d þ 20 mg/d Antitumor activity observed RXR Phase I (n ¼ 12) tamoxifen (PMID 11352969) and recommended phase II dose determined Fenretinide 4-OH RAR Primary prevention: women at Tamoxifen 5 mg/d vs. Low-dose tamoxifen plus Phenylretinamide high risk of breast cancer fenretinide 200 mg/d vs. the fenretinide did not reduce Randomized double-blind combination vs. placebo (58) breast cancer events vs. 2 Â 2 design (n ¼ 235) placebo; numerical reduction in annual odds of breast cancer observed with Clinical Cancer Research both single-agent tamoxifen and fenretinide Secondary prevention: 200 mg/d oral for 5 y with 3 d off No difference in rates of breast Baseline IGF-I/mammographic early breast cancer every month vs. observation cancer in overall population, density, as well as change in Phase III randomized (55) but 35% reduction in events mammographic density did (n ¼ 2,867) in premenopausal women in not predict breast cancer unplanned exploratory events analysis (Continued on the following page) Published OnlineFirst January 15, 2013; DOI: 10.1158/1078-0432.CCR-12-3175 Retinoids in Cancer Prevention and Treatment receptors, they are involved in regulating their partner receptor’s pathways, referred to as nonclassical or nonge- nomic pathways (5). Interestingly, these pathways often regulate processes that have functions opposite to the classical pathway. For example, a study has shown that RA activation of the PPARb/d pathway resulted in upregulation of prosurvival genes (17), contrary to the known differen- tiation function of RARs and RXRs in response to RA. The function of RAs, which involves nongenomic pathways, associated with longer median survival in an unplanned subgroup analysis may provide opportunities for cancer cells to develop resis- Grade 3/4 hypertriglyceridemia Biomarker evaluation tance to RA treatment, discussed later in this review. Anoth- er important function of RARA is the regulation of stem cell differentiation (11). RAs target stem cells via both genomic 6 mo) and nongenomic pathways such as the Notch pathway and > inflammation (10, 11). In summary, RAs and their receptors t for fi play important roles as regulators of critical processes in t rate (complete fi cells. 20% Retinoids and cancer response, partial response, and stable disease of addition of bexarotene to chemotherapy The retinoids have been investigated extensively for the No survival bene prevention and treatment of cancer, predominantly because of their ability to induce cellular differentiation and arrest proliferation. RA-regulated tumor suppressor genes, when expressed, can inhibit tumor growth (21). Among the 3 RARs, RARb has been well known for its tumor-suppressive effects in epithelial cells (5, 8, 22). Exogenous expression of the RARb gene can cause RA-dependent and -independent oral daily (61) Clinical bene /d every 4 wk with apoptosis and growth arrest (23). RARb-induced growth 2 2 arrest and apoptosis is mediated through RARa (24). As RA ligand-bound RARa binds to the RARE on the RARb pro- cisplatin/vinorelbine (52) moter, multiple activator proteins assemble at the site and Dose and schedule (ref.) Study outcome 400 mg/m 200 mg/m result in the upregulation of the RARb gene (5). The expres- sion of RARb results in the transactivation and expression of a number of its target genes that mediate cell differentiation 148) and death (5, 6, 8).
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