Where to Next with Retinoids for Cancer Therapy?

Vol. 7, 2955–2957, October 2001 Clinical Cancer Research 2955

Editorial Where to Next with Retinoids for Cancer Therapy?

Malcolm A. Smith1 and Barry Anderson 13-cis-RA, and 9-cis-RA causes decreased tumor cell prolifer- Pediatric Section, Cancer Therapy Evaluation Program, National ation and morphological differentiation. A Phase 2 trial of single Cancer Institute, Bethesda, Maryland 20892 agent 13-cis-RA demonstrated minimal antitumor response in children with recurrent or progressive neuroblastoma receiving a dose of 100 mg/m2/day (10). However, complete responses The report by Adamson and colleagues describes a Phase 1 were seen among children with residual tumor in the bone trial in children of 9-cis-RA2 (1). This report follows by nearly marrow who were treated in a Phase 1 trial evaluating higher 10 years the report of the pediatric Phase 1 evaluation of ATRA doses of 13-cis-RA given in two-week pulses (maximum toler- and by more than a decade the initial reports that ATRA induced ated dose, 160 mg/m2/day; Ref. 11). Subsequently, improved high remission rates in patients with APL. The authors conclude event-free survival for children with advanced stage neuroblas- their report by noting the continuing challenge of identifying the toma was demonstrated in a Phase 3 study of patients random- optimal retinoid and the optimal way to integrate retinoids into ized after completion of cytotoxic therapy to receive 6 months multiagent treatment regimens. In addressing this challenge, we 2 first briefly summarize those malignancies for which retinoids of maintenance treatment using 13-cis-RA (160 mg/m /day) on have definitively shown therapeutic benefit, and then we discuss the 2-week pulsed schedule (9). The clinical importance of clinical research opportunities for retinoids and how these can 13-cis-RA dosage for antitumor effectiveness has been sug- be prioritized. gested by the lack of 13-cis-RA benefit among children with Three retinoids have proven oncological utility: ATRA, a advanced neuroblastoma randomized to receive a lower daily ϳ 2 naturally occurring retinoid that binds to and activates RAR ␣, dose (0.75 mg/kg/day or 30 mg/m /day) after high-dose chem- ␤, and ␥; 13-cis-RA which likely acts as an ATRA prodrug; and otherapy and autologous stem cell transplant (12, 13). bexarotene (Targretin, LGD1069), which selectively binds and What criteria ought to be used in selecting among these and activates RXR␣, ␤, and ␥. Best defined among the oncological other retinoids for future clinical evaluation? To the extent that indications of retinoids is the use of ATRA for APL. The basis the primary goal of treatment is cure and not palliation, an for the dramatic efficacy of ATRA against APL is the ability of important criterion is the ability of the agent to kill tumor cells pharmacological doses of ATRA to overcome the repression of or to enhance tumor cell killing when combined with other signaling caused by the PML-RAR␣ fusion protein at physio- anticancer drugs. Given this criterion, a group of retinoids of logical ATRA concentrations. Restoration of signaling leads to particular interest are the apoptogenic retinoids, as exemplified differentiation of APL cells and then to postmaturation apopto- by fenretinide [N-(4-hydroxyphenyl) retinamide] and CD437/6- sis (2). A series of randomized clinical trials have defined the [3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid. benefit for combining ATRA with chemotherapy during induc- Fenretinide at micromolar concentrations is able to induce tion therapy and also the utility of using ATRA as maintenance apoptosis in a number of different types of cancer cells, includ- therapy (3–5). ing neuroblastoma (14, 15), non-small cell lung cancer (16), Bexarotene is approved by the FDA for the treatment of cutaneous squamous cell carcinoma (17), and others. Although ␥ cutaneous manifestations of cutaneous T-cell lymphoma in pa- fenretinide appears to be a potent transactivator with RAR and ␤ ␣ ␣ tients whose disease is refractory to at least one prior systemic a moderate activator with RAR (but not RAR and RXR ; therapy (6). Consistent with the RXR specificity of bexarotene, Ref. 18) and can induce RAR-dependent differentiation and ATRA toxicities such as cheilitis and headache appear to be less apoptosis (19, 20), it can also induce apoptosis through RAR- prominent in patients receiving bexarotene (7, 8). independent mechanisms (16, 19, 21). For some cancer cells, the 13-cis-RA improves outcome for children with advanced production of ROS plays a role in fenretinide-induced apoptosis stage neuroblastoma when given at high doses after intensive (16, 17). Retinoids such as ATRA, 13-cis-RA, and 9-cis-RA do consolidation chemotherapy (9). For many years, it has been not induce ROS (15, 22, 23). The induction of ROS is a rapid known that exposure of neuroblastoma cell lines to ATRA, 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 approx- Received 6/27/01; accepted 7/03/01. imately 1 ␮M (25). More recently, Phase 1 studies of fenretinide The costs of publication of this article were defrayed in part by the have demonstrated that much higher doses of fenretinide are payment of page charges. This article must therefore be hereby marked 2 tolerated (Ͼ500 mg/m /day) and that the 5–10-␮M concentra- advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tions required to induce apoptosis in vitro can be achieved in at 1 To whom requests for reprints should be addressed, at Pediatric least some pediatric patients (26). Section, CTEP, Room 7025, EPN, 6130 Executive Boulevard, Bethesda, CD437, like fenretinide, induces apoptosis in a variety of MD 20892. Phone: (301) 496-2522; E-mail: [email protected]. 2 cancer cell types. CD437 selectively binds to and transactivates The abbreviations used are: 9-cis-RA, 9-cis-retinoic acid; ATRA, ␥ all-trans retinoic acid; APL, acute promyelocytic leukemia; RAR, reti- RAR , but is able to induce apoptosis by mechanisms independ- noic acid receptor; 13-cis-RA, 13-cis-retinoic acid; RXR, retinoid X ent of RAR transcriptional activation (27, 28). In lung and receptor; ROS, reactive oxygen species; HDAC, histone deacetylase. prostate cancer cell lines, an apoptosis-inducing CD437 ana- Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2001 American Association for Cancer Research. 2956 Editorial

logue induces expression and mitochondrial translocation of often, preclinical models provide insufficient insight into the transcription factor TR3/Nur77 and induces inner mitochondrial best use of an agent to achieve clinical benefit. Nonetheless, membrane depolarization and mitochondrial release of cyto- decisions concerning prioritizing clinical research opportunities chrome c (29, 30). CD437 can also up-regulate expression of a must be made based on the best available information, however number of apoptosis-related genes, including Killer/DR5, Bax, imperfect that information is. To the extent possible, it will be and Fas (28, 31, 32). This interesting compound has not been important to determine whether the signaling pathways identi- evaluated in the clinical setting. fied as important in preclinical models are indeed modulated in Concerning the use of retinoids in multiagent combina- the clinical setting. This closing of the loop between preclinical tions, of particular interest is the use of retinoids in combination and clinical observations allows confirmation (or refutation) of with HDAC inhibitors. The biological basis for this combination hypotheses concerning critical factors associated with retinoid is the ability of non-liganded RARs to recruit HDAC complexes antitumor activity, thereby permitting more rational applications leading to transcriptional repression of target genes (33). For of retinoids in oncological practice. APL, resistance to ATRA can in some cases be overcome by combination therapy using ATRA with a HDAC inhibitor (34, REFERENCES 35). For some non-promyelocytic cases of acute myelogenous leukemia, the poor sensitivity to retinoid-induced differentiation 1. Adamson, P. C., Widemann, B. C., Reaman, G. H., Seibel, N. L., Murphy, R. F., Gillespie, A. F., and Balis, F. M. A Phase I trial and may reflect HDAC-dependent repression of retinoid signaling pharmacokinetic study of 9-cis-retinoic acid (ALRT1057) in pediatric pa- pathways, and HDAC inhibition can restore ATRA-induced tients with refractory cancer. A joint Pediatric Oncology Branch. NCI and differentiation (36). For neuroblastoma, combination treatment Children’s Cancer Group Study. Clin. Cancer Res., 7: 3034–3039, 2001. (either in vitro or in vivo) of neuroblastoma cells with ATRA 2. Altucci, L., Rossin, A., Raffelsberger, W., Reitmair, A., Chomienne, and a HDAC inhibitor leads to greater antitumor activity than C., and Gronemeyer, H. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand that obtained with either single agent (37, 38). Clinical evalua- TRAIL. Nat. Med., 7: 680–686, 2001. tions of retinoids with HDAC inhibitors have to date been 3. Fenaux, P., Chastang, C., Chevret, S., Sanz, M., Dombret, H., limited to the combination of ATRA with phenylbutyrate (35), Archimbaud, E., Fey, M., Rayon, C., Huguet, F., Sotto, J. J., Gardin, C., but this strategy warrants continued consideration given the Makhoul, P. C., Travade, P., Solary, E., Fegueux, N., Bordessoule, D., availability of new HDAC inhibitors in clinical evaluation [e.g., Miguel, J. S., Link, H., Desablens, B., Stamatoullas, A., Deconinck, E., MS-275, suberoylanilide hydroxamic acid (SAHA), and CI- Maloisel, F., Castaigne, S., Preudhomme, C., and Degos, L. A randomized comparison of all-trans-retinoic acid (ATRA) followed by chem- 994]. otherapy and ATRA plus chemotherapy and the role of maintenance The effective use of ATRA with conventional cytotoxic therapy in newly diagnosed acute promyelocytic leukemia. The Euro- agents for APL (see above) provides proof-of-principle for the pean APL Group. Blood, 94: 1192–1200, 1999. potential utility of combining retinoids with cytotoxic agents. 4. Fenaux, P., Chevret, S., Guerci, A., Fegueux, N., Dombret, H., Combinations of retinoids with conventional cytotoxic agents Thomas, X., Sanz, M., Link, H., Maloisel, F., Gardin, C., Bordessoule, D., Stoppa, A. M., Sadoun, A., Muus, P., Wandt, H., Mineur, P., have shown promise in some preclinical models, including Whittaker, J. A., Fey, M., Daniel, M. T., Castaigne, S., and Degos, L. combinations of 9-cis-RA with cisplatin (39) and combinations Long-term follow-up confirms the benefit of all-trans retinoic acid in of fenretinide with either cisplatin or etoposide (15, 40, 41). The acute promyelocytic leukemia. European APL group. Leukemia (Bal- supra-additive activity of fenretinide in combination with cyto- timore), 14: 1371–1377, 2000. toxic agents appears to be associated with the ability of fen- 5. Tallman, M. S., Andersen, J. W., Schiffer, C. A., Appelbaum, F. R., retinide to induce ROS (15). Feusner, J. H., Ogden, A., Shepherd, L., Willman, C., Bloomfield, C. D., Rowe, J. M., and Wiernik, P. H. All-trans-retinoic acid in acute promyelo- Other retinoid combinations of potential utility include cytic leukemia [see comments; published erratum appears in N. Engl. retinoids plus receptor tyrosine kinase inhibitors (42) and com- J. Med., 337: 1639, 1997]. N. Engl. J. Med., 337: 1021–1028, 1997. binations of fenretinide with modulators of ceramide metabo- 6. Khuri, F. R., Rigas, J. R., Figlin, R. A., Gralla, R. J., Shin, D. M., lism (24). The ability of CD437 to up-regulate DR4 and DR5 Munden, R., Fox, N., Huyghe, M. R., Kean, Y., Reich, S. D., and Hong, death receptor expression in some cancer cell lines suggests the W. K. 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Malcolm A. Smith and Barry Anderson

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