Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs

Abstract

Genomic analyses are defining numerous new targets for cancer therapy. Therapies aimed at specific genetic and epigenetic targets in cancer cells as well as expanded development of immunotherapies are placing increased demands on animal models. Traditional experimental models do not possess the collective features (cancer heterogeneity, molecular complexity, invasion, metastasis, and immune cell response) critical to predict success or failure of emerging therapies in humans. There is growing evidence, however, that dogs with specific forms of naturally occurring cancer can serve as highly relevant animal models to complement traditional models. Invasive urinary bladder cancer (invasive urothelial carcinoma (InvUC)) in dogs, for example, closely mimics the cancer in humans in pathology, molecular features, biological behavior including sites and frequency of distant metastasis, and response to chemotherapy. Genomic analyses are defining further intriguing similarities between InvUC in dogs and that in humans. Multiple canine clinical trials have been completed, and others are in progress with the aim of translating important findings into humans to increase the success rate of human trials, as well as helping pet dogs. Examples of successful targeted therapy studies and the challenges to be met to fully utilize naturally occurring dog models of cancer will be reviewed.

Naturally-Occurring Invasive Urothelial Carcinoma in Dogs, a Unique Model to Drive Advances in Managing Muscle Invasive Bladder Cancer in Humans

“…For patients who are not eligible for cystectomy, bladder sparing therapies combining radiation therapy and chemotherapy have been defined (99). The treatment of InvUC in dogs can include surgery, radiation therapy, chemotherapy and other drugs, or combinations of these, although surgery and radiation therapy are used less often than drug therapy in dogs (30)(31)(32). Complete cystectomy is not typically performed in pet dogs because of the frequent extension of cancer beyond the bladder (urethra, prostate, other organs), the morbidity of the procedure, and the expense involved (30)(31)(32).…”

“…With the resurgence of immunotherapy and the understanding that the immune system plays a major role in the outcomes of many types of therapies (16)(17)(18)(24)(25)(26)(27)(28)(29), it is especially critical that animal models possess a level of immunocompetence similar to that in human cancer patients. There is compelling evidence that dogs with naturally-occurring InvUC possess these collective features and can serve as a highly relevant animal model for the human condition to complement other models (30)(31)(32). This review will summarize the similarities (and differences) between InvUC in dogs and humans, and discuss some of the settings in which the canine model could be most useful.…”

RNAseq expression patterns of canine invasive urothelial carcinoma reveal two distinct tumor clusters and shared regions of dysregulation with human bladder tumors

“…In the past several years canine iUC has been established as a relevant model for the testing and development of targeted drugs that benefit both canine and human patients [3,9,10].. Because of similarities in molecular features, tumor heterogeneity, metastatic behavior, and an immunocompetent host, the dog system closely mimics the human condition. It is, thus, expected that the canine system will predict drug outcomes in humans with high fidelity.…”

Near infrared photoimmunotherapy targeting bladder cancer with a canine anti-epidermal growth factor receptor (EGFR) antibody

“…This will permit the development of instrumentation suitable for translation to humans and will improve the understanding of treatment effects. Dogs with naturally occurring invasive TCC provide an ideal animal model to address this need [ 11 – 13 ].…”