Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation.
Cell
; 156(5): 986-1001, 2014 Feb 27.
Article
in En
| MEDLINE
| ID: mdl-24581497
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 LXRß, which elicits these outcomes through transcriptional induction of tumoral and stromal apolipoprotein-E (ApoE). LXRß agonism robustly suppressed tumor growth and metastasis across a diverse mutational spectrum of melanoma lines. LXRß targeting significantly prolonged animal survival, suppressed the progression of established metastases, and inhibited brain metastatic colonization. Importantly, LXRß 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Skin Neoplasms
/
Orphan Nuclear Receptors
/
Melanoma
/
Neoplasm Metastasis
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell
Year:
2014
Type:
Article
Affiliation country:
United States