Optimizing bexarotene therapy for cutaneous T-cell lymphoma

Talpur, Rakhshandra; Ward, Staci; Apisarnthanarax, Narin; Breuer-McHam, Joan; Duvic, Madeleine

doi:10.1067/mjd.2002.124607

Cited by 173 publications

(140 citation statements)

References 19 publications

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“…Gemfibrozil-treated patients had a 9-fold decrease in melanoma compared with placebo-treated controls, whereas statin-treated patients had a 1.9-fold reduced incidence of melanoma compared with placebo treated controls (36). Fenofibrate also increased the response rate to retinoids in a human clinical trial for cutaneous T cell lymphoma (37), suggesting that PPAR␣ ligands may potentiate the effect of other anticancer agents.…”

Section: Discussionmentioning

confidence: 89%

PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

Panigrahy

Kaipainen

Huang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

244

206

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Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferatoractivated receptor (PPAR)␣ deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPAR␣ would promote tumor growth. Surprisingly, the PPAR␣ agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPAR␣-deficient tumors were still susceptible to fenofibrate, absence of PPAR␣ in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPAR␣ as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPAR␣ agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPAR␣ agonists in cancer treatment, alone and in combination with other therapies. stroma ͉ inflammation ͉ fibrates ͉ microenvironment P eroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors comprising three isoforms, PPAR␣, PPAR␦, and PPAR␥, which act as ligand-activated transcriptional factors. PPARs play key roles in energy homeostasis by modulating glucose and lipid metabolism and transport (1). PPAR␣ is also critical in inflammation (2) and is the molecular target of the fibrate class of drugs, such as fenofibrate, which act as agonistic ligands of PPAR␣.Long-term administration of certain PPAR␣ agonists (clofibrate and WY14643) induces hepatocarcinogenesis in rodents but not in humans (3). Consequently, PPAR␣ has not been established as a molecular target for cancer therapy by its agonistic ligands. In contrast, PPAR␥ and PPAR␦ agonists have been extensively studied to evaluate their anticancer effects because of their antiproliferative, proapoptotic, antiapoptotic, and differentiation-promoting activity (4). However, recent studies have revealed the expression of PPAR␣ in tumor cells (5, 6), and PPAR␣ ligands suppress the growth of several cancer lines, including colon, breast, endometrial and skin, in vitro (7-10). PPAR␣ ligands also suppress the metastatic potential of melanoma cells in vitro and in vivo (11,12). Furthermore, PPAR␣ ligands decrease tumor development in murine colon carcinogenesis (7). Clofibric acid inhibits the growth of human ovarian cancer in mice (13). Most recently, the PPAR␣ agonist WY14643 suppresses tumorigenesis in a PPAR␣-dependent manner (14).Together, these data suggest that PPAR...

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Section: Discussionmentioning

confidence: 89%

PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

Panigrahy

Kaipainen

Huang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

244

206

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“…63,67 Bexarotene is usually administered at 300 mg/m 2 / day and treatment is continued indefinitely in patients who respond. 15,16,68 Bexarotene causes severe central hypothyroidism with high frequency, associated with marked reductions in serum concentrations of thyroid-stimulating hormone and thyroxine. During treatment, patients should be monitored for thyroid function and for hypertriglyceridemia.…”

Section: Rexinoidsmentioning

confidence: 99%

“…15,16,63 Most patients will require concomitant treatment with a lipid-lowering agent. 16,68 Gemfibrozil is contraindicated in this regard because it increases plasma concentrations of bexarotene, presumably due to inhibition of cytochrome P450 3A4, which, in turn, results in a paradoxical elevation of triglycerides. 15,63,68…”

Section: Rexinoidsmentioning

confidence: 99%

EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome

Trautinger

Knobler

Willemze

et al. 2006

European Journal of Cancer

390

308

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“…[6][7][8][9] Retinoids induce IL-12 production, which results in enhanced Th1 activity, whereas the use of interferon alpha/gamma inhibits Th2 cytokine production. 10 Additionally, interferon and retinoids may have synergistic antiangiogenic properties, and both may induce antiproliferative genes. 5 The discovery of a subclass of retinoid receptors, retinoid X receptor (RXR, a, b, and g), led to the development of the RXR agonist bexarotene (Targretin, Ligand Pharmaceuticals, San Diego, Calif).…”

mentioning

confidence: 99%

Results of a Phase II trial of oral bexarotene (Targretin) combined with interferon alfa‐2b (Intron‐A) for patients with cutaneous T‐cell lymphoma

Straus

Duvic

Kuzel

et al. 2007

Cancer

Self Cite

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BACKGROUND.Bexarotene is one of the most active single agents for the treatment of recurring or refractory cutaneous T‐cell lymphoma (CTCL). Interferon alfa has also been used for many years as an effective treatment for this disease. The results in recent case reports of the combination of bexarotene and interferon alfa have been promising. Based on more extensive results reported with the combination of other retinoids with interferon alfa, the present study attempted to determine the response rate, response duration, and safety of bexarotene (Targretin capsules, Ligand Pharmaceuticals, San Diego, Calif) alone and then with the addition of interferon alfa‐2b (Intron‐A, Schering‐Plough, Kenilworth, NJ).METHODS.Patients with biopsy‐proven CTCL, TNM stages IB, IIA, IIB‐IV, were treated with oral bexarotene 300 mg/m2/day for at least 8 weeks. If a complete response was not seen after 8 weeks, interferon alfa‐2b 3 million units (MU) subcutaneously was added, and increased to 5 MU if tolerated, 3 times a week.RESULTS.A total of 22 patients were enrolled at 5 sites, and 18 patients were assessable for response. Overall response rate for combined bexarotene and interferon alfa was 39% (95% confidence interval [CI]: 17%–64%), including 1 patient with a clinical complete response, 6 patients with partial response, 3 patients with stable disease, and 8 patients with progressive disease. Three partial responses were first noted during the bexarotene‐alone phase. Adverse events were generally manageable, and only 1 patient was withdrawn from study for hypertriglyceridemia.CONCLUSIONS.The addition of interferon alfa‐2b did not increase the response rate that would have been expected with bexarotene alone. Cancer 2007. © 2007 American Cancer Society.

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Optimizing bexarotene therapy for cutaneous T-cell lymphoma

Cited by 173 publications

References 19 publications

PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome

Results of a Phase II trial of oral bexarotene (Targretin) combined with interferon alfa‐2b (Intron‐A) for patients with cutaneous T‐cell lymphoma

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