Dogs and humans are the only species in which naturally occurring malignant gliomas are common. Effective therapeutics for malignant glioma represents a major unmet need in medicine, as the prognosis for dogs and humans with malignant gliomas remains poor. We and others have described the clinical, imaging, histomorphologic, and molecular similarities shared between canine and human gliomas. Our collaborative efforts have identified that canine gliomas overexpress interleukin 13 receptor alpha 2 (IL-13RA2), and EphA2/EphA3 analogous to what has been found in human glioblastoma (GBM). Further we have been actively investigating novel methods for loco-regional drug delivery to the brain, such as real-time MRI monitored convection enhanced delivery, photothermotherapy, and electroporation-based approaches, and have demonstrated the safety and feasibility of these therapeutic platforms in dogs with spontaneous gliomas. Core 3 will provide the veterinary clinical and regulatory expertise and support to enable use of client-owned dogs with spontaneous gliomas as a unique and unifying model system for the pre-clinical evaluation and translation of the novel therapeutic approaches developed in Projects 1-4. We will specifically support the projects through three specific aims.
In Aim 1, we will generate IACUC protocols and obtain institutional approvals to harvest canine tissues for use in in vitro experiments, as well as to perform the in vivo clinical studies in client-owned dogs with gliomas described in Specific Aims 3 of both Projects 2 and 3.
In Aim 2, we will collect, clinically annotate, and bank canine glioma tissue specimens. These tissues will be distributed to PPG project investigators to characterize the expression and distribution of IL-13RA2, EphA2, EphA3, and EphB2 receptors in canine glioma for validation of targeting canine gliomas with the QUAD-CTX multivalent and Pep1L-CTX cytotoxins, and optimize the electrical field thresholds required for tumor ablation using high- frequency irreversible electroporation (H-FIRE).
In Aim 3, we will provide the veterinary clinical and neurosurgical expertise necessary to conduct pre-clinical studies to evaluate the ability of our innovative technological platforms, the H-FIRE and convection-enhanced thermo-chemotherapy systems (CETCS), to deliver the novel targeted cytotoxic drug conjugates, QUAD-CTX and Pep-1L-CTX generated in Project 1, to naturally occurring intracranial gliomas in dogs, and to provide procedural training and oversight of the H-FIRE treatment, GBM resection, and convection-enhanced delivery in the rodent models described in Projects 3 and 4.
Canines and humans are the only species in which primary brain tumors are common. This Core will perform pre-clinical studies in which innovative approaches to brain tumor therapy will be investigated. These large and faithful animal models of human disease will greatly facilitate the application of these therapeutic strategies to humans.
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| Sweeney, Daniel C; Weaver, James C; Davalos, Rafael V (2018) Characterization of Cell Membrane Permeability In Vitro Part I: Transport Behavior Induced by Single-Pulse Electric Fields. Technol Cancer Res Treat 17:1533033818792491 |
