Drug Delivery and Treatment of Glioma/Glioblastomas in Dogs

Induced tumor models in rodents have been the mainstay in the development of novel anticancer treatments. However, almost 90% of therapies that cure mice fail to move beyond Phase I/II clinical trials in part due to the complexity of human tumor environment and host immune interactions. Pet dogs with sporadic primary brain tumors recapitulate important features of human disease and may represent a more relevant model to translate new therapies to human GBM patients. The incidence of canine brain tumors, including glioma, is similar to human brain tumors and canine and human patients share similar clinical presentation as well as tumor type, location, and histologic and imaging characteristics. The prognosis for canine and human patients with high-grade glioma is poor despite treatment, however, there is no accepted standard of care for dogs. Recent studies have compared neuropathologic classification, molecular life histories that included genomic, transcriptomic and epigenetic profiling, and systemic and local immune profiles and found striking similarities between canine and human brain tumors. The College of Veterinary Medicine at the University of Minnesota established a Canine Brain Tumor Clinical Trials Program in 2008 that has been led by Dr. Pluhar since its inception.

Our program has received over 30 grants and contracts and has primarily focused on novel immunotherapies to avoid using more toxic therapies like radiation and chemotherapy. All new therapies that were tested in canine patients were first shown to be efficacious in our murine glioma model. Interestingly, some of the combination therapies that improved the response in our murine glioma model such as interferon-g gene therapy added to tumor lysate vaccination or immune checkpoint inhibitor peptide (CD200AR-L) added to thymidine kinase/Flt3L gene therapy have not had any beneficial effect in the canine glioma patients. These results lend support to the idea that dogs with spontaneous tumors may be a more relevant translational model. The majority of papers reporting responses to some therapy in canine brain tumor patients are based on a presumptive diagnosis. One strength of our program is that since surgical debulking to minimize disease load is an integral component of our approach, we have a definitive histologic diagnosis for the brain lesion in every (> 400) canine patients. Similar to others, we have found that ~30% of lesions with characteristics of glioma on MRI are diagnosed as something other than high-grade glioma, which demonstrates the importance of biopsy in these trials.