Where to next with retinoids for cancer therapy?

The report by Adamson and colleagues describes a Phase 1 trial in children of 9-cis-RA (1). This report follows by nearly 10 years the report of the pediatric Phase 1 evaluation of ATRA and by more than a decade the initial reports that ATRA induced high remission rates in patients with APL. The authors conclude their report by noting the continuing challenge of identifying the optimal retinoid and the optimal way to integrate retinoids into multiagent treatment regimens. In addressing this challenge, we first briefly summarize those malignancies for which retinoids have definitively shown therapeutic benefit, and then we discuss clinical research opportunities for retinoids and how these can be prioritized. Three retinoids have proven oncological utility: ATRA, a naturally occurring retinoid that binds to and activates RAR , , and ; 13-cis-RA which likely acts as an ATRA prodrug; and bexarotene (Targretin, LGD1069), which selectively binds and activates RXR , , and . Best defined among the oncological indications of retinoids is the use of ATRA for APL. The basis for the dramatic efficacy of ATRA against APL is the ability of pharmacological doses of ATRA to overcome the repression of signaling caused by the PML-RAR fusion protein at physiological ATRA concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis (2). A series of randomized clinical trials have defined the benefit for combining ATRA with chemotherapy during induction therapy and also the utility of using ATRA as maintenance therapy (3–5). Bexarotene is approved by the FDA for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients whose disease is refractory to at least one prior systemic therapy (6). Consistent with the RXR specificity of bexarotene, ATRA toxicities such as cheilitis and headache appear to be less prominent in patients receiving bexarotene (7, 8). 13-cis-RA improves outcome for children with advanced stage neuroblastoma when given at high doses after intensive consolidation chemotherapy (9). For many years, it has been known that exposure of neuroblastoma cell lines to ATRA, 13-cis-RA, and 9-cis-RA causes decreased tumor cell proliferation and morphological differentiation. A Phase 2 trial of single agent 13-cis-RA demonstrated minimal antitumor response in children with recurrent or progressive neuroblastoma receiving a dose of 100 mg/m/day (10). However, complete responses were seen among children with residual tumor in the bone marrow who were treated in a Phase 1 trial evaluating higher doses of 13-cis-RA given in two-week pulses (maximum tolerated dose, 160 mg/m/day; Ref. 11). Subsequently, improved event-free survival for children with advanced stage neuroblastoma was demonstrated in a Phase 3 study of patients randomized after completion of cytotoxic therapy to receive 6 months of maintenance treatment using 13-cis-RA (160 mg/m/day) on the 2-week pulsed schedule (9). The clinical importance of 13-cis-RA dosage for antitumor effectiveness has been suggested by the lack of 13-cis-RA benefit among children with advanced neuroblastoma randomized to receive a lower daily dose (0.75 mg/kg/day or 30 mg/m/day) after high-dose chemotherapy and autologous stem cell transplant (12, 13). What criteria ought to be used in selecting among these and other retinoids for future clinical evaluation? To the extent that the primary goal of treatment is cure and not palliation, an important criterion is the ability of the agent to kill tumor cells or to enhance tumor cell killing when combined with other anticancer drugs. Given this criterion, a group of retinoids of particular interest are the apoptogenic retinoids, as exemplified by fenretinide [N-(4-hydroxyphenyl) retinamide] and CD437/6[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid. Fenretinide at micromolar concentrations is able to induce apoptosis in a number of different types of cancer cells, including neuroblastoma (14, 15), non-small cell lung cancer (16), cutaneous squamous cell carcinoma (17), and others. Although fenretinide appears to be a potent transactivator with RAR and a moderate activator with RAR (but not RAR and RXR ; Ref. 18) and can induce RAR-dependent differentiation and apoptosis (19, 20), it can also induce apoptosis through RARindependent mechanisms (16, 19, 21). For some cancer cells, the production of ROS plays a role in fenretinide-induced apoptosis (16, 17). Retinoids such as ATRA, 13-cis-RA, and 9-cis-RA do not induce ROS (15, 22, 23). The induction of ROS is a rapid cellular response to fenretinide exposure (17, 20, 23) and is not dependent on RAR activation (20, 22). Induction of ceramide synthesis may also play a role in fenretinide-induced apoptosis (14, 24). The initial clinical trials of fenretinide used relatively low doses (200 mg/day) that achieved serum levels of approximately 1 M (25). More recently, Phase 1 studies of fenretinide have demonstrated that much higher doses of fenretinide are tolerated ( 500 mg/m/day) and that the 5–10M concentrations required to induce apoptosis in vitro can be achieved in at least some pediatric patients (26). CD437, like fenretinide, induces apoptosis in a variety of cancer cell types. CD437 selectively binds to and transactivates RAR , but is able to induce apoptosis by mechanisms independent of RAR transcriptional activation (27, 28). In lung and prostate cancer cell lines, an apoptosis-inducing CD437 anaReceived 6/27/01; accepted 7/03/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at Pediatric Section, CTEP, Room 7025, EPN, 6130 Executive Boulevard, Bethesda, MD 20892. Phone: (301) 496-2522; E-mail: [email protected]. 2 The abbreviations used are: 9-cis-RA, 9-cis-retinoic acid; ATRA, all-trans retinoic acid; APL, acute promyelocytic leukemia; RAR, retinoic acid receptor; 13-cis-RA, 13-cis-retinoic acid; RXR, retinoid X receptor; ROS, reactive oxygen species; HDAC, histone deacetylase. 2955 Vol. 7, 2955–2957, October 2001 Clinical Cancer Research