title: Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo.
abstract: Transcription factors are important targets for the treatment of a variety of malignancies but are extremely difficult to inhibit, as they are located in the cell's nucleus and act mainly by protein-DNA and protein-protein interactions. The transcriptional regulators Id1 and Id3 are attractive targets for cancer therapy as they are required for tumor invasiveness, metastasis and angiogenesis. We report here the development of an antitumor agent that downregulates Id1 effectively in tumor endothelial cells in vivo. Efficient delivery and substantial reduction of Id1 protein levels in the tumor endothelium were effected by fusing an antisense molecule to a peptide known to home specifically to tumor neovessels. In two different tumor models, systemic delivery of this drug led to enhanced hemorrhage, hypoxia and inhibition of primary tumor growth and metastasis, similar to what is observed in Id1 knockout mice. Combination with the Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin yielded virtually complete growth suppression of aggressive breast tumors.
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, New York 10021, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Henke
authors.forename: Jonathan
authors.initials: J
authors.lastname: Perk
authors.forename: Jelena
authors.initials: J
authors.lastname: Vider
authors.forename: Paola
authors.initials: P
authors.lastname: de Candia
authors.forename: Yvette
authors.initials: Y
authors.lastname: Chin
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.forename: Luca
authors.initials: L
authors.lastname: Cartegni
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D018390:Gene Targeting / Q000379:methods*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics*; D010455:Peptides / Q000008:administration & dosage / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D010455:Peptides; D014157:Transcription Factors