The protein comes from the parasite that causes pregnancy-associated malaria; its role here is to bind a particular sugar chain on cells in the placenta. This has now been joined to an extremely toxic molecule, with the protein guiding the killer molecule to cancer cells and binding to a specific sugar molecule.
“This sugar is only expressed in the placenta under normal circumstances, but we have discovered that this sugar is also expressed in many types of cancer cells,” said Mads Daugaard, project leader at the University of British Columbia.
“Cancer and placenta tissue have features in common. The placenta is an organ that grows to about 500 grams in 40 weeks, it has a high proliferation rate and it needs to invade adjacent tissue during pregnancy.”
The malarial protein – VAR2CSA – was successfully conjugated chemically to a compound called hemiasterlin; this localised to tumours in mice and strongly inhibited tumour cell growth and metastasis.
“VAR2 Pharmaceuticals partnered with a Vancouver based biotech company, Kairos Therapeutics, as they have a proprietary drug conjugation platform that they normally use to make antibody-drug conjugates. We were able to conjugate the highly toxic hemiasterlin compound to the protein and test it on tumor cells,” Daugaard explained.
This toxin is found naturally in sea sponges; analogues of this compound have been tested in the clinic. It is known to target a specific phase of the cell lifecycle, lock into that one state and promote cell death.
“You only need one or two compounds in a cell to kill it,” said Daugaard, who says the protein-toxin conjugate was well tolerated in the animal model.
Daugaard and his colleague Ali Salanti set up a company in 2012 – Copenhagen-based VAR2 Pharmaceuticals – to develop the malaria protein for cancer research
“We have tested hundreds of cancer cell lines and the vast majority has this specific onco-fetal CSA [the sugar molecule] and binds VAR2CSA [the malarial protein],” noted co-author Ali Salanti, parasitologist at the University of Copenhagen, Denmark. “And we have tested thousands of patient biopsies also showing the presence of onco-fetal CSA with no binding in normal tissue or normal cells.”
The plan is to develop this into a therapeutic compound that can be tested in humans within a 4-year time frame, but also develop this into a diagnostic technology. They also will investigate why tumors start to express this molecule and whether this could be prevented.