Phase I/II Trial of Urokinase Plasminogen Activator-Targeted Oncolytic Newcastle Disease Virus for Canine Intracranial Tumors.

Neurotropic oncolytic viruses are appealing agents to treat brain tumors as they penetrate the blood-brain barrier and induce preferential cytolysis of neoplastic cells. The pathobiological similarities between human and canine brain tumors make immunocompetent dogs with naturally occurring tumors attractive models for the study of oncolytic virotherapies. In this dose-escalation/expansion study, an engineered Lasota NDV strain targeting the urokinase plasminogen activator system (rLAS-uPA) was administered by repetitive intravenous infusions to 20 dogs with intracranial tumors with the objectives of characterizing toxicities, immunologic responses, and neuroradiological anti-tumor effects of the virus for up to 6 months following treatment. Dose-limiting toxicities manifested as fever, hematologic, and neurological adverse events, and the maximum tolerated dose (MTD) of rLAS-uPA was 2 × 107 pfu/mL. Mild adverse events, including transient infusion reactions, diarrhea, and fever were observed in 16/18 of dogs treated at or below MTD. No infectious virus was recoverable from body fluids. Neutralizing antibodies to rLAS-uPA were present in all dogs by 2 weeks post-treatment, and viral genetic material was detected in post-treatment tumors from six dogs. Tumor volumetric reductions occurred in 2/11 dogs receiving the MTD. Systemically administered rLAS-uPA NDV was safe and induced anti-tumor effects in canine brain tumors, although modifications to evade host anti-viral immunity are needed to optimize this novel therapy.

Case Report: MRI, Clinical, and Pathological Correlates of Bromethalin Toxicosis in Three Dogs.

Bromethalin toxicosis is an increasingly common clinical presentation in dogs that may be fatal depending on the extent of intoxication. Antemortem diagnosis of bromethalin toxicosis was achieved in three dogs by demonstration of the active metabolite desmethylbromethalin in fat or serum. Magnetic resonance imaging (MRI) findings were consistent with a diffuse leukoencephalopathy with restricted diffusion and prominent involvement of the corticospinal motor tracts on T2-weighted and diffusion-weighted sequences. Imaging findings were confirmed in one non-surviving dog at necropsy. Resolution of MRI abnormalities was demonstrated in one surviving dog that was consistent with the associated resolution of clinical signs. Initial findings in these dogs support further investigation of specific MRI patterns in cases of leukoencephalopathy to aid differential diagnosis. While antemortem detection of bromethalin and its metabolites confirms exposure, quantitation may be informative as a prognostic biomarker.

Expression and activity of the urokinase plasminogen activator system in canine primary brain tumors.

BACKGROUND: The expression of the urokinase plasminogen activator receptor (uPAR), a glycosylphosphatidylinositol-anchored protein family member, and the activity of its ligand, urokinase-type plasminogen activator (uPA), have been associated with the invasive and metastatic potentials of a variety of human brain tumors through their regulation of extracellular matrix degradation. Domesticated dogs develop naturally occurring brain tumors that share many clinical, phenotypic, molecular, and genetic features with their human counterparts, which has prompted the use of the dogs with spontaneous brain tumors as models to expedite the translation of novel brain tumor therapeutics to humans. There is currently little known regarding the role of the uPA system in canine brain tumorigenesis. The objective of this study was to characterize the expression of uPAR and the activity of uPA in canine brain tumors as justification for the development of uPAR-targeted brain tumor therapeutics in dogs. METHODS: We investigated the expression of uPAR in 37 primary canine brain tumors using immunohistochemistry, Western blotting, real-time quantitative polymerase chain reaction analyses, and by the assay of the activity of uPA using casein-plasminogen zymography. RESULTS: Expression of uPAR was observed in multiple tumoral microenvironmental niches, including neoplastic cells, stroma, and the vasculature of canine brain tumors. Relative to normal brain tissues, uPAR protein and mRNA expression were significantly greater in canine meningiomas, gliomas, and choroid plexus tumors. Increased activity of uPA was documented in all tumor types. CONCLUSIONS: uPAR is overexpressed and uPA activity increased in canine meningiomas, gliomas, and choroid plexus tumors. This study illustrates the potential of uPAR/uPA molecularly targeted approaches for canine brain tumor therapeutics and reinforces the translational significance of canines with spontaneous brain tumors as models for human disease.