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Making a malaria protein to kill cancer cells

Ali Salanti med sin malaria og kræft studier på Københavns Universitet

While developing a malaria vaccine for pregnant women, scientists at the University of Copenhagen Department of Immunology and Microbiology found an unique molecule. Cancer researchers had been searching for something like it for decades.

The molecule, explains Professor Ali Salanti, leader of the research group, is a certain chondroitin sulfate (CS), a modified carbohydrate. The Salanti group found the CS because it is abundant on placental cells and strongly and specifically bound by VAR2CSA, a protein made by the malaria parasite. A literature search about the CS went in an unexpected direction, says Salanti: “We found that it has a functional role in cancer.”

A Cancer Cell paper with Mads Daugaard’s group at the University of British Columbia, among others, lays out the discovery and its implications. Similarities between placental/fetal cells and cancer cells, invasion, migration, rapid growth, have been studied for decades. But Salanti et al. found a distinct molecular connection between the cell types. The paper shows that VAR2CSA binds cells with the placental CS, which includes most cancerous but not normal cells.

Exploiting VAR2CSA-tumor binding

The applications of a protein that selectively targets malignant cells are clear. Salanti et al. show that recombinant VAR2CSA linked to a toxin delivers the cell-killing drug to cancer cells. In mouse models of cancers from prostate to lymphoma, the VAR2CSA-toxin conjugate shrinks tumors and extends survival compared to untreated controls. The findings are the basis of the angel investor-funded company, VAR2 Pharmaceuticals, cofounded by Salanti, Daugaard, and coauthor Dr. Thor G. Theander.

“The spearhead program of VAR2,” says Salanti, “is the drug conjugate.” VAR2CSA binds 95% of cancer cell lines tested so it has broad therapeutic potential. Salanti says the company is also exploring using VAR2CSA for radiotherapy. Another possibility is immunotherapy in which a cancer patient’s T cells are removed, engineered to express VAR2CSA, and reintroduced into the patient’s blood. Now, rather than delivering a toxin to cancer cells, VAR2CSA delivers cancer cell-killing T cells. VAR2CSA can also detect the cancer-specific CS in blood and urine for potential assays for diagnosis, prognosis, and treatment monitoring.

Salanti is realistic about VAR2’s prospects. “First, we need to optimize protein expression,” he says, “so we expect clinical trials in about four years.” He stresses that although mouse model results are promising, effects in humans are unknown. Still, the results support a longheld belief that similarities between placental/fetal cells and malignancy will lead to cancer breakthroughs, making VAR2 Pharmaceuticals a company to watch.

REFERENCE:

Salanti A, Clausen TM, Agerbæk MØ, Al Nakouzi N, Dahlbäck M, Oo HZ, Lee S, Gustavsson T, Rich JR, Hedberg BJ, Mao Y, Barington L, Pereira MA, LoBello J, Endo M, Fazli L, Soden J, Wang CK, Sander AF, Dagil R, Thrane S, Holst PJ, Meng L, Favero F, Weiss GJ, Nielsen MA, Freeth J, Nielsen TO, Zaia J, Tran NL, Trent J, Babcook JS, Theander TG, Sorensen PH, Daugaard M. Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. Cancer Cell. 2015 12;28(4):500-14.

 

Photo of Ali Salanti. Photographer: Kristian Brasen

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