chondroitin-sulfates and hemiasterlin

Although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy and chemoresistance remains a major challenge in this disease setting.. To investigate the clinical significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy.. An ofCS-binding recombinant VAR2CSA protein derived from the malaria parasite Plasmodium falciparum (rVAR2) was used as an in situ, in vitro, and in vivo ofCS-targeting reagent in cisplatin-resistant MIBC. The ofCS expression landscape was analyzed in two independent cohorts of matched pre- and post-NAC-treated MIBC patients.. An rVAR2 protein armed with cytotoxic hemiasterlin compounds (rVAR2 drug conjugate [VDC] 886) was evaluated as a novel therapeutic strategy in a xenograft model of cisplatin-resistant MIBC.. Antineoplastic effects of targeting ofCS.. In situ, ofCS was significantly overexpressed in residual tumors after NAC in two independent patient cohorts (p<0.02). Global gene-expression profiling and biochemical analysis of primary tumors and cell lines revealed syndican-1 and chondroitin sulfate proteoglycan 4 as ofCS-modified proteoglycans in MIBC. In vitro, ofCS was expressed on all MIBC cell lines tested, and VDC886 eliminated these cells in the low-nanomolar IC. Targeting ofCS provides a promising second-line treatment strategy in cisplatin-resistant MIBC.. Cisplatin-resistant bladder cancer overexpresses particular sugar chains compared with chemotherapy-naïve bladder cancer. Using a recombinant protein from the malaria parasite Plasmodium falciparum, we can target these sugar chains, and our results showed a significant antitumor effect in cisplatin-resistant bladder cancer. This novel treatment paradigm provides therapeutic access to bladder cancers not responding to cisplatin.

Topics: Animals; Antigens, Protozoan; Antineoplastic Agents; Biomarkers, Tumor; British Columbia; Cell Death; Cell Line, Tumor; Chondroitin Sulfates; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Europe; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Kaplan-Meier Estimate; Mice; Oligopeptides; Time Factors; Treatment Outcome; Tumor Burden; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays

Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification.

Topics: Animals; Antigens, Protozoan; Cell Line, Tumor; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Female; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Hyaluronan Receptors; Melanoma, Experimental; Membrane Proteins; Mice; Molecular Targeted Therapy; Oligopeptides; Organ Specificity; Placenta; Pregnancy; Recombinant Proteins; Skin Neoplasms