Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma

Connolly, Nina P.; Shetty, Amol C.; Stokum, Jesse A.; Hoeschele, Ina; Siegel, Marni B.; Miller, C. Ryan; Kim, Anthony J.; Ho, Cheng‐Ying; Dávila, Eduardo; Simard, J. Marc; Devine, Scott E.; Rossmeisl, John H.; Holland, Eric C.; Winkles, Jeffrey A.; Woodworth, Graeme F.

doi:10.1038/s41598-018-19451-6

Cited by 22 publications

(26 citation statements)

References 76 publications

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“…Phosphorylated members of the PI3K/AKT/MTOR and RAS/MAPK-pathways are seen more commonly in astrocytic tumors than oligodendrogliomas or undefined gliomas (93, 96). When canine and human glioma molecular signatures are compared, it is clear that there is an abundance of heterogeneity amongst these two species as it relates to gliomagenesis (97). 1p/19q co-deletion, which is common in human gliomas, is absent in the dog (94, 95).…”

Section: Gliomamentioning

confidence: 99%

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

2019

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In the dog, primary intracranial neoplasia represents ~2–5% of all cancers and is especially common in certain breeds including English and French bulldogs and Boxers. The most common types of primary intracranial cancer in the dog are meningioma, glioma, and choroid plexus tumors, generally occurring in middle aged to older dogs. Much work has recently been done to understand the characteristic imaging and clinicopathologic features of these tumors. The gross and histologic landscape of these tumors in the dog compare favorably to their human counterparts with many similarities noted in histologic patterns, subtype, and grades. Data informing the underlying molecular abnormalities in the canine tumors have only begun to be unraveled, but reveal similar pathways are mutated between canine and human primary intracranial neoplasia. This review will provide an overview of the clinicopathologic features of the three most common forms of primary intracranial cancer in the dog, delve into the comparative aspects between the dog and human neoplasms, and provide an introduction to current standard of care while also highlighting novel, experimental treatments that may help bridge the gap between canine and human cancer therapies.

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Section: Gliomamentioning

confidence: 99%

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

2019

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“…Upregulated CCL2 (MCP-1), IFNG , and IL10 gene expression were observed in gliomas from dogs enrolled in this trial. 35 …”

Section: Discussionmentioning

confidence: 99%

Phase I trial of convection-enhanced delivery of IL13RA2 and EPHA2 receptor targeted cytotoxins in dogs with spontaneous intracranial gliomas

et al. 2020

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Background The interleukin 13 receptor alpha 2 (IL13RA2) and ephrin type-A receptor 2 (EPHA2) receptors are attractive therapeutic targets, being expressed in ~90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met with technical barriers associated with the convection enhanced delivery (CED) method. In this study, IL-13 mutant and Ephrin-A1 (EFNA1)-based bacterial cytotoxins targeted to IL13RA2 and EPHA2 receptors, respectively, were administered locoregionally by CED to dogs with intracranial gliomas to evaluate their safety and preliminary efficacy. Methods In this Phase I , 3 + 3 dose escalation trial, cytotoxins were infused by CED in 17 dogs with gliomas expressing IL13RA2 or EPHA2 receptors. CED was performed using a shape-fitting therapeutic planning algorithm, reflux-preventing catheters, and real-time intraoperative MRI-monitoring. The primary end point was to determine the maximum tolerated dose of the cytotoxic cocktail in dogs with gliomas. Results Consistent intratumoral delivery of the cytotoxic cocktail was achieved, with a median target coverage of 70% (range, 40-94%). Cytotoxins were well tolerated over a dose range of 0.012-1.278 μg/mL delivered to the target volume (median, 0.099 μg/mL), with no dose limiting toxicities observed. Objective tumor responses, up to 94% tumor volume reduction, were observed in 50% (8/16) of dogs, including at least one dog in each dosing cohort >0.05 μg/mL. Conclusions This study provides pre-clinical data fundamental to the translation of this multi-receptor targeted therapeutic approach to the human clinic.

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“…Compared to rodent models and humans, the repertoire of validated reagents for molecular biological investigations is restricted for companion animals; this is particularly true for feline models. The current level of understanding of the genetic alterations that define companion animal diseases is also limited, and the identification of species-specific drivers of neurological disease is inevitable ( LeBlanc et al, 2016 ; Connolly et al, 2018 ). Historically, the ability of translational studies in companion animals to truly inform human clinical trials has been hampered by a lack of statistical power or inclusion of controls that receive a validated standard of care treatment.…”

Section: Introductionmentioning

confidence: 99%

Companion animal models of neurological disease

Partridge

Rossmeisl

2020

Journal of Neuroscience Methods

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Clinical translation of novel therapeutics that improve the survival and quality of life of patients with neurological disease remains a challenge, with many investigational drug and device candidates failing in advanced stage clinical trials. Naturally occurring inherited and acquired neurological diseases, such as epilepsy, inborn errors of metabolism, brain tumors, spinal cord injury, and stroke occur frequently in companion animals, and many of these share epidemiologic, pathophysiologic and clinical features with their human counterparts. As companion animals have a relatively abbreviated lifespan and genetic background, are immunocompetent, share their environment with human caregivers, and can be clinically managed using techniques and tools similar to those used in humans, they have tremendous potential for increasing the predictive value of preclinical drug and device studies. Here, we review comparative features of spontaneous neurological diseases in companion animals with an emphasis on neuroimaging methods and features, illustrate their historical use in translational studies, and discuss inherent limitations associated with each disease model. Integration of companion animals with naturally occurring disease into preclinical studies can complement and expand the knowledge gained from studies in other animal models, accelerate or improve the manner in which research is translated to the human clinic, and ultimately generate discoveries that will benefit the health of humans and animals.

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Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma

Cited by 22 publications

References 76 publications

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

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

Phase I trial of convection-enhanced delivery of IL13RA2 and EPHA2 receptor targeted cytotoxins in dogs with spontaneous intracranial gliomas

Companion animal models of neurological disease

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