Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Cancer cell, 2015, 28.4: 500-514

Speaker: Jia-Yian Woo (武珈言)                         Time: 13:10-14:00, Mar 30, 2016

Commentator: Dr. Jyh-Wei Shin (辛致煒)     Place: Room 601

Abstract

The malaria parasite, Plasmodium falciparum, can modify infected red blood cells (RECs) to present the malarial protein, VAR2CSA, which binds to cells in the placenta. This acts as an anchor, preventing the infected cells from traveling to the spleen where they would be destroyed ^[1]. The presentation of Pregnancy-associated malaria (PAM) is particularly life-threatening to both mother and developing fetus. IHC staining revealed that placenta-specific chondroitin sulfate A (CSA) was present on the plasma membrane or in the surrounding stroma of various tumor tissues. Both recombinant V5-tagged VAR2CSA (rVAR2) and erythrocytes infected with P. falciparum expressing VAR2CSA can bind to various patient-derived cancer cells but not to normal cells, and this interaction was decreased by the addition of soluble CSA to the medium. The Retrogenix cell microarray technology revealed that the presence of placenta-type CS groups in 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 was modified,  indicating the potential to exploit this interaction as a mechanism to target cancer cells. Together, these data suggest that rVAR2 can be utilized to facilitate intracellular delivery of cytotoxic compounds to pl-CS expressing cells in vivo. The clinical limitation of using drugs and natural toxins as a cancer therapy is often due to their toxicity. Notably, administration of drug conjugates in which rVAR2 was fused to either diphtheria toxin or an analog of the antimitotic peptide hemiasterlin (KT886), a marine sponge extract, was markedly more potent than administrating diphtheria toxin or KT886 alone and selectively killed various tumor cells but not normal cells both in vitro and in vivo without inducing detectable toxicity in normal tissues. These findings indicate that fusing cytotoxic drugs to VAR2CSA may enable more targeted drug delivery to tumors.

References

1.     Baruch et al. (1995). Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82, 77–87.