Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part V: Clinically Relevant Model for Testing New Therapeutic Approaches
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ABSTRACT
A significant obstacle to the development of new brain tumor therapeutics remains the lack of rodent models that faithfully reproduce the in vivo complexities of human glioblastoma. Dogs and humans are the only species that frequently develop spontaneous brain tumors. Remarkable clinical, phenotypic, and molecular similarities exist between human and canine malignant glioma. Our research has focused on the development of pharmacologically tractable molecular targets common to human and canine gliomas, as well as the discovery and refinement of novel methods of drug delivery to the brain, such as convection-enhanced delivery (CED), irreversible electroporation (IRE), and focused ultrasound, that can overcome the limitations imposed by the blood–brain and blood–tumor barriers. Through the conduct of early phase clinical trials in dogs, we demonstrate the safety, feasibility, and preliminary efficacies of IL-13RA2- and EphA2-targeted bacterial cytotoxins and IRE for the treatment of spontaneous malignant glioma, illustrate the clinical utility of real-time imaging monitored CED as a robust drug delivery platform, and describe the use of the tumor-bearing dog in transcranial-focused ultrasound applications related to neuro-oncology. The dog brain cancer model offers unique opportunities to expedite the clinical translation of cancer therapeutics through the design of preclinical investigations that ask and answer drug and medical device development questions that cannot be sufficiently addressed in rodent models.
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