Chordoma Foundation

HIF-1α

Hypoxia-inducible Factor 1-alpha (HIF-1α) is a transcription factor that plays a role in cellular response to low oxygen situations (hypoxia).Location: Chromosome 14q23.2
HIF1α expression directs the expression of a number of genes with a roles in tumor progression, influencing cell growth, proliferation, and apoptosis. Hyperactivation of HIF1α has been linked to tumor progression and poor prognosis in a number of cancers.1

HIF-1α in Chordoma

Intratumoral hypoxia is characteristic of solid tumors like chordoma, and HIF-1α protein levels rapidly increase in response to hypoxic conditions.1 HIF-1α expression is indeed detected most chordoma samples that have been tested, and its inhibition has been evaluated in a chordoma cell line. Research into this target is ongoing, but this page contains a summary of published research into the role of HIF-1α in chordoma.

Molecular Evidence


Gene and Protein Expression

  • HIF-1α gene and protein expression have been detected in the majority of chordoma samples analyzed and in chordoma cell line CM-319.1 2 Protein expression is correlated with the expression of multidrug resistance-associated protein (MRP1); researchers suggest that HIF-1α may play a role in multidrug resistance to chemotherapy.2
  • HIF-1α expression correlated with VEGF and MMP-2 expression, suggesting that HIF-1α may influence expression of these key players in angiogenesis.1 MMP-2 has been correlated with poorer prognosis and increased bone invasion in chordoma patients, and miR-1237-3p, shown to target MMP-2, has been shown to be down regulated in chordoma tissues.3

Preclinical Evidence


In-vitro Efficacy

  • LBH-589 + Imatinib: A report that inhibition of HIF-1α with HDAC inhibitor LBH-589 in concert with PDGFR inhibitor Imatinib brought promising results in-vitro (overcoming PTEN loss of heterozygosity, a loss that is linked to tumorigenesis) provides the basis for an ongoing phase I clinical trial exploring the efficacy of this combination of therapies in chordoma patients.4
  • Hypoxia and LBH-589: Hypoxic conditions increased HIF-1α expression in the cell line UCH-1 and treatment with HDAC inhibitor LBH589 in hypoxic conditions led to a reduction of HIF-1α levels. 5


References

1.
Li X, Ji Z, Ma Y, Qiu X, Fan Q, Ma B. Expression of hypoxia-inducible factor-1α, vascular endothelial growth factor and matrix metalloproteinase-2 in sacral chordomas. Oncol Lett. 2012;3(6):1268-1274. [PubMed]
2.
Ji Z, Long H, Hu Y, et al. Expression of MDR1, HIF-1α and MRP1 in sacral chordoma and chordoma cell line CM-319. J Exp Clin Cancer Res. 2010;29:158. [PubMed]
3.
Zou M, Huang W, Wang X, et al. Reduced expression of miRNA-1237-3p associated with poor survival of spinal chordoma patients. Eur Spine J. 2015;24(8):1738-1746. [PubMed]
4.
Williams B, Raper D, Godbout E, et al. Diagnosis and treatment of chordoma. J Natl Compr Canc Netw. 2013;11(6):726-731. [PubMed]
5.
Lee D, Zhang Y, Kassam A, et al. Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma. PLoS One. 2015;10(8):e0134426. [PubMed]