Hybridon sees broader use for cancer drug
much broader range of human cancers than previously thought,
according to new research.
GEM240 is already in preclinical development for tumours that are characterised by mutations in the gene coding for p53, a protein that blocks the development of cancer and is implicated in around half of all human malignancies. But new research published in the Journal of Biological Chemistry reveals that GEM240 could also be of value in the remaining 50 per cent by targeting a different pathway.
p53 prevents the development of cancer in cells by exerting tight control over cell replication. It is also known that p53 is inhibited by another molecule, called MDM2, and one research track has concentrated on blocking the binding of this factor to restore p53 function. GEM240 targets MDM2 and has previously been shown to interact directly with p53, but the new study reveals that it also decreases the activity of the tumor suppressor protein p21 through direct physical interaction.
The role of the p21 protein in the tumour suppression pathway includes inhibition of cell proliferation and modulation of apoptosis or programmed cell death, in which malignant cells are prompted to self-destruct.
"These findings suggest that the use of antisense therapeutics to block synthesis of MDM2 may have antitumour activity across a broad spectrum of human cancers, regardless of p53 status," commented a spokesman for Hybridon.
The company also believes that its antisense approach to MDM2 could have advantages over small molecules designed to block the oncoprotein. "In contrast to antisense, small molecule inhibitors of MDM2 activity based on the p53-MDM2 interaction might not be effective at simultaneously blocking MDM2 binding to p21," it suggests.
Ruiwen Zhang, associate professor at the University of Alabama at Birmingham in the US and one of the lead authors in the study, said: "Our current paper establishes in cellular models that MDM2 binds directly to p21 and facilitates proteasome-mediated p21 degradation, which is the biochemical mechanism that destroys p21 activity."
