The devastating global effects of malaria have been widely documented, but the presentation of the disease during pregnancy is particular troubling and confounding to researchers. Women living in endemic areas face a much greater risk of contracting malaria when they are pregnant, and associated complications once infected with the parasite. While an average adult residing within a malaria endemic region possesses some immunity to the parasite, pregnancy causes complications that leave women and fetuses extremely vulnerable.
In particular, the most virulent species of the malaria parasite, Plasmodium falciparum, modifies human erythrocytes upon invasion and expresses an array of proteins that are transported to the surface of the red blood cell. The major function of these proteins is to bind onto endothelial tissue in the periphery of the systemic circulation, affording the parasite time to grow out of site from the immune system.
Some these parasite-derived red blood cell surface proteins have an affinity for carbohydrate residues found on the surface of cells lining blood vessels. Specifically, a chondroitin sulfate found to accumulate within small spaces of the placenta. Surprisingly, this same residue has been seen to cluster on the surface of various cancers.
Now, a collaborative team of researchers from the Translational Genomics Research Institute (TGen), University of Copenhagen, University of British Columbia (UBC), Vancouver Coastal Health and the BC Cancer Agency, found that the malaria protein, called VAR2CSA, could be used to target anti-cancer drugs and carry them to tumors expressing the specific carbohydrate residue.
“Based on our clinical data, we helped validate that this could be applied to melanoma and lung cancers,” explained co-author Nhan Tran, Ph.D., associate professor in TGen's Cancer and Cell Biology Division. “This specific type of developmental protein—oncofetal chondroitin sulfate—is expressed in the placenta, and is also expressed in lung cancer and melanoma.”
The findings from this study were published recently in Cancer Cell through an article entitled “Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein.”
“Scientists have spent decades trying to find biochemical similarities between placenta tissue and cancer, but we just didn't have the technology to find it,” noted project leader Mads Daugaard, Ph.D., assistant professor of urologic science at UBC and a senior research scientist at the Vancouver Prostate Centre, part of the Vancouver Coastal Health Research Institute. “When my colleagues discovered how malaria uses VAR2CSA to embed itself in the placenta, we immediately saw its potential to deliver cancer drugs in a precise, controlled way to tumors.”
The researchers created a recombinant VAR2CSA protein that was fused with either diphtheria toxin or conjugated to hemiasterlin (a microtubule inhibitor) and saw strong inhibition of tumor cell growth and metastasis in vivo.
“This is an extraordinary finding that paves the way for targeting sugar molecules in pediatric and adulthood human cancer, and our groups are vigorously pursuing this possibility together,” said co-senior investigator Poul Sorensen, M.D., Ph.D., UBC professor of pathology and laboratory medicine.
The researchers were excited by their findings and are currently working with pharmaceutical companies to develop the compound for clinical trial in humans.
“There is some irony that a disease as destructive as malaria might be exploited to treat another dreaded disease,” stated lead author Ali Salanti, Ph.D., professor of immunology and microbiology in the Centre for Medical Parasitology, at the University of Copenhagen.