Abstract 3798: A glycan-binding malaria protein provides therapeutic access to cisplatin-resistant bladder cancer
Authors: OO HTOO ZARNI , Seiler Roland , Lee Sherry S. , Tortora Davide , Kumar Gunjan , Wang Chris , Clausen Thomas M. , Agerbæk Mette Ø. , Rich Jamie R. , Babcook John S. , Black Peter C. , Salanti Ali , Daugaard Mads 
Published: July 2016

Bladder cancer is a disease of compelling morbidity and mortality mainly due to its high recurrence rate. Cisplatin-based chemotherapy is an integral part of muscle invasive bladder cancer (MIBC) treatment. Although responses are common, a significant number of patients develop resistance to cisplatin and second line treatment options are not well established. No improvement of the MIBC treatment strategy has been achieved in the past two decades and therefore; new approaches to systemic therapy are urgently needed.

The Plasmodium falciparum host-cell anchor protein VAR2CSA has been evolutionarily optimized to bind distinctly modified chondroitin sulfate (CS) glycosaminoglycan (GAG) chains expressed exclusively in the mammalian placenta. This is the underlying key event behind pregnancy-associated malaria outbreaks in endemic regions of the world. We have recently discovered that placental-type CS chains are re-expressed in the malignant compartment as a secondary oncofetal CS (ofCS) modification (Salanti et al. 2015, Cancer Cell). In the present study, we have analyzed the expression and role of ofCS in cisplatin-resistant bladder cancer and evaluated the potential of a VAR2-drug conjugate (VDC) to target cisplatin-resistant tumors.

Using recombinant VAR2CSA protein (rVAR2) as an ofCS detection reagent, we analyzed a tissue microarray of 52 chemotherapy-naïve MIBC samples, with 36 matched post-chemotherapy cystectomy specimens from patients receiving neoadjuvant gemcitabine/cisplatin. In chemoresistant tumor specimens, of-CS expression was significantly upregulated in residual patient tumors after neoadjuvant chemotherapy (p = 0.001) and it was associated with advanced tumor stage (ypT3/4, p = 0.005) and poor overall survival (p = 0.04). Microarray analysis of primary human bladder tumors and subsequent in situ proximity ligation assay validation identified S100A9 and CD44 as the major ofCS-modified proteoglycans in chemoresistant bladder cancer. Binding of rVAR2 to ofCS chains on bladder cancer cells facilitated rapid internalization of the protein. Moreover, a rVAR2-drug conjugate (VDC) efficiently killed all bladder cancer cells in the low nanomolar IC50 concentration range in vitro and retarded growth of chemoresistant orthotopic MIBC xenografts in vivo.

In summary, we demonstrate how a glycan-binding malaria protein can be utilized to gain therapeutic access to cisplatin-resistant bladder cancer. Thus, we provide a method to target cancer-specific glycan modifications for therapeutic intervention as a second line treatment in MIBC, not responding to cisplatin.

Citation Format: HTOO ZARNI OO, Roland Seiler, Sherry S. Lee, Davide Tortora, Gunjan Kumar, Chris Wang, Thomas M. Clausen, Mette Ø. Agerbæk, Jamie R. Rich, John S. Babcook, Peter C. Black, Ali Salanti, Mads Daugaard. A glycan-binding malaria protein provides therapeutic access to cisplatin-resistant bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3798.