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

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 breedassociated risk for InvUC in dogs (e.g., 20-fold increased risk in Scottish Terriers) Knapp et al. Canine Bladder Cancer-Translational Model 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.

Molecular targets for anticancer therapies in companion animals and humans: what can we learn from each other?

“…EGFR is overexpressed in both human and canine invasive transitional cell carcinoma (TCC) in about 75% of the cases 17 , 46 , 47 . Several EGFR-targeting compounds have been or are currently evaluated in clinical trials of human TCC, but so far with mixed results 17 . Recently, a particular 67-gene signature has been associated with sensitivity to EGFR inhibition in human bladder cancer cell lines 48 .…”

Longitudinal assessment of B-RAF V595E levels in the peripheral cell-free tumor DNA of a 10-year-old spayed female Korean Jindo dog with unresectable metastatic urethral transitional cell carcinoma for monitoring the treatment response to a RAF inhibitor (sorafenib)

“…1 Due to its high malignancy, invasiveness, and metastatic potential, TCC is difficult to treat in dogs, despite the availability of intensive multimodal therapies, including surgery, chemotherapy, radiation therapy, and palliative laser ablation. 2,3 Particularly, in dogs with urethral TCC, complete surgical excision is unrewarding because of the location of the tumor, and thus, drugs are the main treatment modality for canine urethral TCC. 4 To our knowledge, there currently is no effective longterm single therapy for the treatment of urethral TCC in dogs; thus, the development of novel therapeutic strategies for urethral TCC, including molecular-targeted therapy, is highly anticipated.…”

Dog leukocyte antigen‐88*034:01 presents nonamer peptides from canine distemper virus hemagglutinin, large polymerase, and matrix proteins

“…It is a realistic possibility that pet dogs ( Canis lupus familiaris ) will play an expanding role in such testing, given the parallels of some naturally‐arising canine cancers, such as osteosarcoma, glioma, urothelial carcinoma and non‐Hodgkin lymphoma (NHL), to their human counterparts (reviewed in Refs. 1‐8). Studies with CAR T cells and PD‐1/PD‐L1 blockade have been reported 9‐11 .…”