title: Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation.
abstract: Melanoma metastasis is a devastating outcome lacking an effective preventative therapeutic. We provide pharmacologic, molecular, and genetic evidence establishing the liver-X nuclear hormone receptor (LXR) as a therapeutic target in melanoma. Oral administration of multiple LXR agonists suppressed melanoma invasion, angiogenesis, tumor progression, and metastasis. Molecular and genetic experiments revealed these effects to be mediated by LXRβ, which elicits these outcomes through transcriptional induction of tumoral and stromal apolipoprotein-E (ApoE). LXRβ agonism robustly suppressed tumor growth and metastasis across a diverse mutational spectrum of melanoma lines. LXRβ targeting significantly prolonged animal survival, suppressed the progression of established metastases, and inhibited brain metastatic colonization. Importantly, LXRβ activation displayed melanoma-suppressive cooperativity with the frontline regimens dacarbazine, B-Raf inhibition, and the anti-CTLA-4 antibody and robustly inhibited melanomas that had acquired resistance to B-Raf inhibition or dacarbazine. We present a promising therapeutic approach that uniquely acts by transcriptionally activating a metastasis suppressor gene.
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Pencheva
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Buss
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Posada
authors.affiliation: Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA. Electronic address: stavazoie@mail.rockefeller.edu.
authors.forename: Sohail F
authors.initials: SF
authors.lastname: Tavazoie
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001565:Benzoates / Q000008:administration & dosage; D001596:Benzylamines / Q000008:administration & dosage; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage; D000071518:Liver X Receptors; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage; D014158:Transcription, Genetic; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001057:Apolipoproteins E; D001565:Benzoates; D001596:Benzylamines; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides