Dogs are man's best friend: in sickness and in health

Abstract

With the median survival of 14.6 months following best available standard of care, malignant gliomas (MGs) remain one of the biggest therapeutic challenges of the modern time. Although the last several decades have witnessed tremendous advancement in our understanding of MG and evolution of many successful preclinical therapeutic strategies, even the most successful preclinical therapeutic strategies often fail to cross the phase I/II clinical trial threshold. One of the significant, but less commonly discussed, barriers in developing effective glioma therapy is the lack of a robust preclinical model. For the last 30 years, rodent orthotopic xenograft models have been extensively used in the preclinical setting. Although they provide a good basic model for understanding tumor biology, their value in successfully translating preclinical therapeutic triumph into clinical success is extremely poor. Companion dogs, which share the same environmental stress as their human counterparts, also spontaneously develop MGs. Dog gliomas that develop spontaneously in an immunocompetent host are very similar to human gliomas and potentially provide a stronger platform for validating the efficacy of therapeutic strategies proven successful in preclinical mouse models. Integrating this model can accelerate development of effective therapeutic options that will benefit both human subjects and pet dogs.

Keywords: canine glioma; comparative oncology; glioblastoma; malignant glioma; spontaneous glioma.

Fig. 1.

Translational gap. Most preclinical studies that progress to human clinical trial fail at phase I/II stage. This failure is most likely due to the large translational gap between a orthotopic xenograft murine model and a complex immunocompetent human host. Comparative oncology provides an ideal platform to bridge this gap.

Fig. 2.

Canine glioma histology. (A) Anaplastic astrocytoma with pleomorphism, anisokaryosis, nuclear atypia, and mitotic activity. (B) GFAP staining of anaplastic astrocytoma. (C) High-grade oligodendroglioma composed of ovoid to fusiform cells and endothelial vascular proliferation. (D) Olig2 immunohistochemistry demonstrates strong nuclear positivity of more than 90% of neoplastic cells. Images courtesy of Dr Miller, Purdue Veterinary Medicine.

Fig. 3.

Common signaling pathways. Spontaneously occurring canine glioma share several molecular abnormalities with human glioma. PDGFRA, platelet derived growth factor receptor alpha.

Fig. 4.

Human and canine glioma on MRI imaging. (A, B) Classical human high-grade glioma with the hallmark ring-enhancing lesion. (C, D) Canine high-grade gliomas that can also show similar ring-enhancing pattern on contrast T1 sequence MRI. (E, F) Human oligodendroglioma with minimal to no contrast enhancement and T2 signal changes. (G, H) Canine oligodendroglioma with T2 signal changes and minimal contrast enhancement.

Fig. 5.

Effect of treatment on human and canine glioma on MRI imaging. Human and canine high-grade oligodendroglioma. (A, Ac) T2-weighted image, a hyperintense and heterogeneous mass is present. (B, Bc) Surgical photo during craniectomy and gross total resection. (C, Cc) Three-month postoperative MRI, complete remission. (D, Dc) Nine-month postoperative MRI, early recurrence. Stereotactic radiosurgery was performed. (E, Ec) Fifteen-month postoperative MRI (4 months after radiosurgery), a small, highly T2-hyperintense area is suggestive of encephalomalacia rather than persistent tumor.

Fig. 6.

Model of integrative approach to neuro-oncology. Strategic collaboration between the basic science researchers, veterinarians, clinicians, and clinician scientists can provide a robust model for neuro-oncological discoveries and advancement that will benefit both human and canine populations.