Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part V: Clinically Relevant Model for Testing New Therapeutic Approaches

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 Canine Brain Tumor Models 406 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 bloodbrain 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.

Canine Primary Intracranial Cancer: A Clinicopathologic and Comparative Review of Glioma, Meningioma, and Choroid Plexus Tumors

“…This will facilitate the routine and systematic characterization of the histomorphologic and molecular features of canine brain cancers, the continuing global comparative genomic analyses of human and veterinary nervous system neoplasms, and the hosting of comprehensively annotated clinicopathological and neuroradiological data registries. These needs have been further recognized by the neurooncology community, and have begun to be addressed by several projects being conducted by the NCI Comparative Brain Tumor Consortium (193, 211). The NCI Comparative Brain Tumor Consortium was the driving force behind the categorization of canine glioma and has recently embarked on a similar goal of redefining the pathologic features of canine meningioma (78).…”

Companion animal models of neurological disease

“…In dogs, 30–50% of all canine neuroepithelial tumors are classified as oligodendrogliomas, compared to only 10–15% of all human neuroepithelial tumors, however high grade oligodendrogliomas predominate in dogs ( Koehler et al, 2018 ). The most frequent glioma subtype encountered in humans is astrocytoma, accounting for 60–70% of all neuroepithelial tumors, of which the majority are grade IV (glioblastoma) ( Dolecek et al, 2012 ; Rossmeisl, 2017 ). Despite these differences, canine gliomas share a number of immunohistochemical characteristics with their human counterpart.…”

“…5 ) ( Saito and Tominaga, 2017 ; Dickinson et al, 2010 ). Irreversible electroporation (IRE) is a non-thermal ablation method that relies on short, intense, monopolar pulses to ablate tumor tissue ( Rossmeisl, 2017 ; Garcia et al, 2012 ; Garcia et al, 2017 ; Ellis et al, 2011 ; Rossmeisl et al, 2013a ). Transient disruption of the blood brain barrier outside the zone of ablation following IRE delivery provides an opportunity for therapeutic delivery to microscopic tumor cells extending beyond visible tumor margins, a major source of disease recurrence ( Garcia et al, 2012 ; Hjouj et al, 2012 ).…”

Identification of cephalomannine as a drug candidate for glioblastoma via high-throughput drug screening

“…Glioblastoma (GBM) is the most common and invasive malignant primary brain tumor in adults 1,2) . Its prognosis remains poor, even with the current standard of care, i.e., a combination of surgery, radiotherapy, and chemotherapy 3,4) .…”