Canine High-Grade Glioma: A Translational Model of Temozolomide Resistance in Human Glioblastoma Multiforme?

Introduction: Glioblastoma Multiforme (GBM) is the deadliest and most common intracranial malignancy in humans. Despite years of research, overall survival for patients with GBM remains dismal. Standard treatment of GBM features surgical resection followed by radiotherapy and chemotherapy, where temozolomide (TMZ) is the first-line agent. While TMZ has been a breakthrough agent in increasing patient survival, the mutation-prone nature of GBM often leads to acquired resistance to TMZ, particularly upon tumor recurrence.

Modeling the complexities of GBM, including acquired resistance to TMZ, has thus posed a unique challenge. The search for a satisfactory preclinical model has led to identification of pet dogs with sporadic gliomas as a translational model of real promise. In addition to sharing many environmental exposures with their owners, dogs present with gliomas at a similar frequency, metabolize certain key drugs analogously, and feature many of the same oncogenic alterations.

Methods: Genomic analysis through RNA sequencing was performed on tumor tissue from pet dogs with high-grade glioma taken during tumor resection. For generating networks, a data set containing gene identifiers and corresponding expression values was uploaded into Ingenuity Pathway Analysis. Each identifier was mapped to its corresponding object in Ingenuity’s Knowledge Base. A fold change cutoff of ±2 and p-value < 0.05 was set to identify molecules whose expression was significantly differentially regulated.

Results: Genomic analysis of our cohort of pet dogs with high-grade glioma (n = 29) revealed the significant dysregulation of sixteen genes known to contribute to TMZ resistance in human GBM, including: SNAI1, FOXS1, LOXL2, LUM, BGN, FABP5, SPAG16, KCNA6, CCD6160, PHGDH, DEGS2, ZBED8, DCT, SPAST, ABDH10, and TTPA.

Conclusion : To our knowledge, this is the first description of transcriptional similarities between human and canine glioma as it pertains to TMZ resistance. While further investigation is needed, we believe this may corroborate the use of the dog as a translational oncologic model in the study of glioma and provide opportunities for the development of novel immunotherapeuties that confer greater susceptibility to TMZ in canines and humans.