Retrogenix detects binding via post-translational modifications

Malaria-host interaction study unveils broad cancer target strategy

Research aimed at understanding the mechanism by which one form of malaria specifically attacks the placenta in pregnant women has resulted in the discovery of a potential new therapy that could be effective in a wide range of cancers. A large international team – which included scientists from Retrogenix – collaborated in the study, which sparked wide media interest following its publication in the leading journal Cancer Cell.

The malaria parasite, Plasmodium falciparum, can modify red blood cells so that they produce a protein, VAR2CSA, which binds to cells in the placenta. This acts as an anchor, preventing the infected cells from travelling to the spleen where they would be destroyed. This can be life threatening for both mother and foetus.

VAR2CSA anchors via a unique type of chondroitin sulphate (CS) chain known to be expressed in the placenta but not in other tissues. Unexpectedly, the group also detected VAR2CSA binding – and expression of the same distinct CS signature – in a high proportion of tumour samples that were tested. This supports the hypothesis that the CS groups are associated with rapid proliferation, vascularisation and invasion of surrounding tissues – characteristics shared by both placenta and tumour cell types.

Retrogenix technology identified the interactions mediated by post-translational modifications

The Retrogenix cell microarray technology was used to determine that the placenta-type CS groups were linked to a number of cell surface proteoglycans, including CD44 and CSPG4. Expression of these proteins varied across tissue types, however, binding of the malaria protein only occurred when the placenta-type CS modification was present indicating the potential to exploit this interaction as a mechanism to target cancer cells. This was confirmed when a recombinant form of the parasite protein fused to a cytotoxic compound showed strong inhibition of in vivo tumour growth and survival without affecting normal tissue.

This is the first published study detailing how the Retrogenix technology can detect and confirm an interaction that specifically involves a post-translational modification. This shows the real advantage over traditional protein arrays which lack the physiological processing that enables proteins to be properly folded, glycosylated and multimerised prior to screening.

The work was led by Ali Salanti at the University of Copenhagen. The paper is entitled: ‘Targeting human cancer by a glycosaminoglycan binding malaria protein.’ For a link to the abstract and full text options please click here.

“We are delighted to have contributed to this finding, bringing the team one step closer to the development of broadly acting new cancer treatment.”

Jo Soden, Executive Director of Retrogenix

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