Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation

Cell. 2014 Feb 27;156(5):986-1001. doi: 10.1016/j.cell.2014.01.038.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Benzoates / administration & dosage
  • Benzylamines / administration & dosage
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Hydrocarbons, Fluorinated / administration & dosage
  • Liver X Receptors
  • Melanoma / drug therapy*
  • Melanoma / pathology
  • Melanoma / secondary*
  • Mice
  • Neoplasm Metastasis / drug therapy*
  • Neoplasm Metastasis / pathology
  • Orphan Nuclear Receptors / agonists*
  • Signal Transduction
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / pathology
  • Sulfonamides / administration & dosage
  • Transcription, Genetic

Substances

  • Apolipoproteins E
  • Benzoates
  • Benzylamines
  • GW 3965
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Sulfonamides
  • TO-901317

Associated data

  • GEO/GSE48782