EntreMed and NCI in cancer collaboration
the National Cancer Institute (NCI) to evaluate the role of
HIF-1alpha inhibition in the treatment of cancer. The agreement
aims to establish the relationship between Entremed's lead compound
and the inhibition of tumour growth.
HIF-1alpha has become a primary target in the fight against cancer, having firmly established its role in HIF-1alpha in tumour proliferation is over-expressed in more than 70 per cent of human tumours and HIF-1alpha over-expression correlates with tumour aggressiveness, metastases and poor prognosis.
EntreMed, a clinical-stage pharmaceutical company developing therapeutics for cancer and inflammatory diseases, aims to investigate the mechanism of its lead compound, 2-methoxyestradiol (2ME2) and a second-generation analog of 2ME2.
2ME2 is an orally active small molecule that attacks tumor cells through multiple mechanisms of action including inducing apoptosis, inhibiting angiogenesis, and disrupting microtubules.
Analogs of 2ME2, developed by EntreMed scientists by modifying its chemical structure, have demonstrated enhanced anti tumour and antiangiogenic properties and improved metabolism while retaining 2ME2's multiple mechanisms of action.
One of these analogs - ENMD-1198, inhibits tumour hypoxia factor-1 alpha (HIF-1alpha) in human cell lines. Additionally, animal tumour models will be used to establish the relationship between levels of 2ME2 in blood or tumour tissue and the inhibition of tumour growth.
"We are pleased to have the opportunity to work with the National Cancer Institute and their team of experts in the field of tumour hypoxia," commented Carolyn Sidor, EntreMed vice president and chief medical officer.
"We believe that 2ME2 has the potential to be a unique cancer therapy by attacking tumours that are dependent on the pro-angiogenic activity of HIF-1alpha."
Preclinical studies have demonstrated that 2ME2 is a potent inhibitor of HIF-1alpha, and its down-regulation is closely associated with 2ME2's tubulin inhibitor properties.
HIF-1alpha is over-expressed in more than 70 per cent of human tumours and HIF-1alpha over-expression correlates with tumour aggressiveness, metastases and poor prognosis.
2ME2 attacks tumours on multiple fronts, directly by disrupting microtubules, an intracellular matrix necessary for the rapid division of cancer cells (mitosis), by inducing programmed cell death (apoptosis), and by blocking blood vessels that feed tumours (angiogenesis inhibition).
"Studies performed will enhance our understanding of the mechanism of action by which 2ME2 and ENMD-1198 inhibit HIF-1alpha in human tumours," added Sidor.
EntreMed is currently evaluating several formulations of 2ME2 (Panzem Capsules and Panzem NCD) in Phase I and II clinical oncology studies.
Results from these and other 2ME2 mechanism studies forms part of its ongoing Panzem clinical development program. The company is also conducting IND-directed studies with ENMD-1198 and plans to submit an IND to the FDA for this compound later this year.
