An Oncofetal Glycosaminoglycan Modification Provides Therapeutic Access to Cisplatin-Resistant Bladder Cancer
This week’s featured publication of the Week comes out of the lab of Dr. Mads Daugaard of the Vancouver Prostate Centre.
Can you provide a brief overview of your lab’s current research focus?
My team focuses on development of novel innovative technology for cancer therapeutics and diagnostics. A major focus of the lab is on the identification of oncofetal proteins and secondary protein modifications such as glycosylation’s that can be potentially exploited as cancer targets in the clinic. We are more technology focused than disease focused in the sense that we are generally trying to deploy our discoveries across multiple cancer indications when possible. On the therapeutic side, we are working with diverse technologies including small molecule drugs, protein-drug conjugates, bi-specific therapeutic proteins, and cell-based immunotherapies. For diagnostics, we focus on developing novel platform technologies for isolating circulating tumor cells and cancer stem cells, as well as assays detecting urine-based biomarkers in a number of different human cancers.
What is the significance of the findings in this publication?
In this particular publication we uncovered a specific type of placental chondroitin sulfate glycosaminoglycan re-expressed as an oncofetal event in bladder cancer. We were able to detect this glycan using a recombinant protein derived from the malaria parasite Plasmodium falciparum with high inherent affinity for placental-type chondroitin sulfate.
The malaria protein used in our study is called VAR2CSA and the normal function of this protein is to anchor malaria-infected red blood cells to chondroitin sulfate proteoglycans expressed exclusively in the placental syncytium. This event leads to specific placental parasite sequestration and is the key molecular event behind pregnancy-associated malaria outbreaks in endemic regions of the world.
Because placental cells and cancer tumors share this glycan modification, we were able to conveniently re-purpose the malaria protein for specific cancer targeting. We found that this particular oncofetal glycan was attached to a limited number of proteoglycans on bladder cancer cells as well as on cells in the tumor stroma. Due to the immense clinical need for new second line treatment options, we focused specifically on advanced bladder cancers not responding to standard of care chemotherapy. We found that chemotherapy-resistant tumors in fact up-regulated oncofetal chondroitin sulfate modifications of proteins. In an animal model recapitulating human chemotherapy-resistant bladder cancer, we were able to completely impair tumor growth using a toxin-conjugated form of VAR2CSA, with the ability to deliver a cytotoxic payload to tumors without harming normal organs. In summary, we developed a first-in-class glycan-targeting drug derived from a malaria protein with the potential of offering a second shot against chemotherapy-resistant bladder cancer.
Briefly, what are the next steps for this research?
We are putting more and more effort into research that will give us a better understanding of the regulation and function of oncofetal chondroitin sulfate glycan’s in human cancer. Over the next 2-3 years the protein-drug conjugate will be developed towards the clinical arena in collaboration with industry partners. The VAR2 technology is not only relevant for bladder cancer but also for many other high-risk childhood and adult cancers. At present, we have not yet decided on what type of cancer to first test in phase I clinical trial using our protein-drug conjugate, but chemotherapy-resistant bladder is an interesting candidate. In parallel, we are developing companion diagnostic technologies that we hope can help stratify patients for the clinical trials.
This project was supported by:
The Vancouver Prostate Centre
The European Research Council
Vancouver Coastal Health Research Institutes
The Danish Cancer Society