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

Deborah W Knapp,Sagar Utturkar,José A Ramos-Vara,Christopher M Fulkerson,Timothy L Ratliff,Gregory M Cresswell,Breann C Sommer,Deepika Dhawan,Noah M Hahn

doi:10.3389/fonc.2019.01493

Abstract

There is a great need to improve the outlook for people facing urinary bladder cancer, especially for patients with invasive urothelial carcinoma (InvUC) which is lethal in 50% of cases. Improved outcomes for patients with InvUC could come from advances on several fronts including emerging immunotherapies, targeted therapies, and new drug combinations; selection of patients most likely to respond to a given treatment based on molecular subtypes, immune signatures, and other characteristics; and prevention, early detection, and early intervention. Progress on all of these fronts will require clinically relevant animal models for translational research. The animal model(s) should possess key features that drive success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). Experimental animal models, while essential in bladder cancer research, do not possess these collective features to accurately predict outcomes in humans. These key features, however, are present in naturally-occurring InvUC in pet dogs. Canine InvUC closely mimics muscle-invasive bladder cancer in humans in cellular and molecular features, molecular subtypes, immune response patterns, biological behavior (sites and frequency of metastasis), and response to therapy. Thus, dogs can offer a highly relevant animal model to complement other models in research for new therapies for bladder cancer. Clinical treatment trials in pet dogs with InvUC are considered a win-win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. In addition, the high breed-associated risk for InvUC in dogs (e.g., 20-fold increased risk in Scottish Terriers) offers an unparalleled opportunity to test new strategies in primary prevention, early detection, and early intervention. This review will provide an overview of canine InvUC, summarize the similarities (and differences) between canine and human InvUC, and provide evidence for the expanding value of this canine model in bladder cancer research.

Highlights

Urinary bladder cancer is a major human health issue worldwide with more than 400,000 new cases per year [1, 2]
Folate receptor alpha expression was detected in 78% of canine invasive urothelial carcinoma (InvUC) tissues, and folate uptake in vivo was confirmed by scintigraphy
An intriguing discovery was made in dogs with InvUC and other types of cancer which is expected to translate into benefit in humans

Summary

Introduction

Urinary bladder cancer (urothelial carcinoma, referred to as transitional cell carcinoma) is a major human health issue worldwide with more than 400,000 new cases per year [1, 2]. Non-infiltrating tumors comprise the majority of human InvUCs (≥65% of cases), this form of bladder cancer is uncommon in dogs. Using a different approach to exploit EGFR expression, a study of an EGFR-targeted toxin has recently been reported with antitumor activity observed in dogs with InvUC [78].

Results

Conclusion