EntreMed Inc., a clinical-stage pharmaceutical company developing therapeutics primarily for the treatment of cancer and inflammatory diseases, achieved positive preclinical results for ENMD-1198, an analog of 2-methoxyestradiol (2ME2). The data were presented by EntreMed scientists during an oral presentation at the International Tumour Metabolism Summit held last week in Genova, Italy.

Oral administration of ENMD-1198 showed pronounced in vivo anti-tumour activity in preclinical models of human cancer. Oral daily treatment with ENMD-1198 in an orthotopic MDA MB 231 breast cancer model led to the disruption of microtubules within tumour cells and a substantial decrease in cells staining positively for HIF-1a. HIF-10 is over-expressed in more than 70% of human tumours and its over-expression correlates with tumour aggressiveness, metastases and poor prognosis, claims a company release.

Protein levels for two additional transcription factors, NFkB and Stat3, known to modulate HIF-10 protein levels in vitro, were also reduced following daily oral ENMD-1198 treatment as determined by decreased nuclear staining for active transcription factor proteins. In addition to their relationship to HIF-1a protein, the three transcription factors are known to regulate multiple genes and their proteins that contribute to tumour growth and progression.

Serum proteins regulated by HIF-1a, NFkB and Stat3, were also reduced substantially following oral administration of ENMD-1198 in a preclinical orthotopic breast cancer model

ENMD-1198 is a new chemical entity (NCE) based on a modified chemical structure of 2ME2 designed to increase anti-tumour and antiangiogenic properties and improve metabolism, while retaining 2ME2's multiple mechanisms of action. These mechanisms include inducing apoptosis, binding microtubules, and inhibiting HIF-1a. ENMD-1198 represents a second generation of 2ME2-like molecules with potential for broad application in cancer and other diseases.

Carolyn F. Sidor, EntreMed vice president and chief medical officer, commented on the study results, "ENMD-1198 is a novel molecule with potent anti-tumour and antiangiogenic properties. These data provide valuable information regarding the potential importance of HIF-1a inhibition in the treatment of human cancers. ENMD-1198 continues our commitment to developing anti-cancer drugs with dual anti-tumour and antiangiogenic properties."

Hypoxia-inducible factor 1 (HIF-1) is a protein composed of two subunits - HIF-1a and HIF-1ß. HIF-1 mediates tumour cell responses to changes in oxygen concentration and belongs to a class of molecules termed transcription (transfer of genetic code) factors.