Hypoxia-inducible factor-1 (HIF-1) is a
transcription factor that plays a critical role in angiogenesis, survival,
metastasis, drug resistance, and
glucose metabolism. Elevated expression of the alpha-subunit of HIF-1 (HIF-1alpha), which occurs in response to
hypoxia or activation of
growth factor pathways, is associated with poor prognosis in many types of
cancer. Therefore, down-regulation of HIF-1alpha
protein by
RNA antagonists may control
cancer growth.
EZN-2968 is a
RNA antagonist composed of third-generation
oligonucleotide,
locked nucleic acid, technology that specifically binds and inhibits the expression of HIF-1alpha
mRNA. In vitro, in human prostate (15PC3, PC3, and DU145) and
glioblastoma (U373) cells,
EZN-2968 induced a potent, selective, and durable antagonism of HIF-1
mRNA and
protein expression (IC(50), 1-5 nmol/L) under normoxic and hypoxic conditions associated with inhibition of
tumor cell growth. Additionally, down-regulation of HIF-1alpha
protein by
EZN-2968 led to reduction of its transcriptional targets and of human umbilical vein endothelial cell tube formation. In vivo, administration of
EZN-2968 to normal mice led to specific, dose-dependent, and highly potent down-regulation of endogenous HIF-1alpha and
vascular endothelial growth factor in the liver. The effect can last for days after administration of single dose of
EZN-2968 and is associated with long residence time of
locked nucleic acid in certain tissues. In efficacy studies,
tumor reduction was found in nude mice implanted with DU145 cells treated with
EZN-2968. Ongoing phase I studies of
EZN-2968 in patients with advanced
malignancies will determine optimal dose and schedule for the phase II program.