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Molecularly Targeted Cytotoxins

Many of the conventional chemotherapeutic drugs used in clinical practice are relatively non-specific with regards to their cellular “targets”. Essentially, these agents will kill or otherwise alter all cells that are exposed to adequate drug concentrations. The clinical consequences of this non-specific action is that most chemotherapeutic agents result in damage to or death of normal, healthy cells in addition to cancerous cells. It is these effects on healthy cells that give rise to the notorious and systemic adverse effects associated with chemotherapy.

Modern cancer research has been heavily devoted to the development of chemotherapeutic drugs that are specifically designed to trigger cell death by “targeting” unique aspects of cancer cells, such as cell surface proteins, that differentiate them from normal cells. Some targeted therapeutics, such as tyrosine kinase inhibitors, are used in human and veterinary clinical practice and have shown promise in the treatment of a number of cancers. In conjunction with the molecular therapeutics laboratory directed by Dr. Waldemar Debinski at the Thomas K. Hearn Brain Tumor Research Center at the Wake Forest School of Medicine, we have identified and generated monoclonal antibodies against two cell surface proteins, IL-13Rα2 and EPHA2, that are expressed on the majority of canine gliomas but are not present in normal canine brain tissue (Figure 2). By conjugating genetically modified bacterial cytotoxins to these monoclonal antibodies, we have developed a molecularly targeted drug delivery platform with potent and specific activity against brain cancer cells that will spare normal brain tissue. Because these targeted cytotoxins are relatively large molecules that will not cross the blood-brain-barrier, they must be delivered directly into the tumor using a technique called Convection Enhanced Delivery (CED). The specificity of our chemotherapeutic agent for cancer cells combined with the use of image-guided CED allows us to effectively target the brain tumor while simultaneously minimizing adverse local and systemic effects to healthy tissues.

Similar patterns of IL-13Rα2 and EPHA2 protein expression have been observed in human gliomas. Our preliminary work suggests that we have identified a unique molecular signature for gliomas that is shared by both dogs and humans. This clinical trial is intended to generate clinical data that can be used for the continued development of molecularly targeted cytotoxins as a potential therapy in human gliomas.

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