Identification of a naturally-occurring canine model for early detection and intervention research in high grade urothelial carcinoma

Deepika Dhawan; José A Ramos-Vara; Sagar M Utturkar; Audrey Ruple; Sarah A Tersey; Jennifer B Nelson; Bruce R Cooper; Hock Gan Heng; Elaine A Ostrander; Heidi G Parker; Noah M Hahn; Larry G Adams; Christopher M Fulkerson; Michael O Childress; Patty L Bonney; Christine Royce; Lindsey M Fourez; Alexander W Enstrom; Lisbeth A Ambrosius; Deborah W Knapp

doi:10.3389/fonc.2022.1011969

Identification of a naturally-occurring canine model for early detection and intervention research in high grade urothelial carcinoma

Front Oncol. 2022 Nov 11:12:1011969. doi: 10.3389/fonc.2022.1011969. eCollection 2022.

Authors

Deepika Dhawan¹, José A Ramos-Vara^{2

3}, Sagar M Utturkar³, Audrey Ruple^{3

4}, Sarah A Tersey⁵, Jennifer B Nelson⁵, Bruce R Cooper⁶, Hock Gan Heng¹, Elaine A Ostrander⁷, Heidi G Parker⁷, Noah M Hahn⁸, Larry G Adams¹, Christopher M Fulkerson^{1

2}, Michael O Childress^{1

2}, Patty L Bonney¹, Christine Royce¹, Lindsey M Fourez¹, Alexander W Enstrom¹, Lisbeth A Ambrosius¹, Deborah W Knapp^{1

3}

Affiliations

¹ Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States.
² Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States.
³ Purdue University Center for Cancer Research, West Lafayette, IN, United States.
⁴ Department of Public Health, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States.
⁵ Department of Medicine, Section of Endocrinology, Metabolism, and Diabetes, University of Chicago, Chicago, IL, United States.
⁶ Bindley Bioscience Center, Purdue University, West Lafayette, IN, United States.
⁷ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.
⁸ Department of Oncology and Urology, Johns Hopkins University School of Medicine, and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.

Abstract

Background: Early detection and intervention research is expected to improve the outcomes for patients with high grade muscle invasive urothelial carcinoma (InvUC). With limited patients in suitable high-risk study cohorts, relevant animal model research is critical. Experimental animal models often fail to adequately represent human cancer. The purpose of this study was to determine the suitability of dogs with high breed-associated risk for naturally-occurring InvUC to serve as relevant models for early detection and intervention research. The feasibility of screening and early intervention, and similarities and differences between canine and human tumors, and early and later canine tumors were determined.

Methods: STs (n=120) ≥ 6 years old with no outward evidence of urinary disease were screened at 6-month intervals for 3 years with physical exam, ultrasonography, and urinalysis with sediment exam. Cystoscopic biopsy was performed in dogs with positive screening tests. The pathological, clinical, and molecular characteristics of the "early" cancer detected by screening were determined. Transcriptomic signatures were compared between the early tumors and published findings in human InvUC, and to more advanced "later" canine tumors from STs who had the typical presentation of hematuria and urinary dysfunction. An early intervention trial of an oral cyclooxygenase inhibitor, deracoxib, was conducted in dogs with cancer detected through screening.

Results: Biopsy-confirmed bladder cancer was detected in 32 (27%) of 120 STs including InvUC (n=29, three starting as dysplasia), grade 1 noninvasive cancer (n=2), and carcinoma in situ (n=1). Transcriptomic signatures including druggable targets such as EGFR and the PI3K-AKT-mTOR pathway, were very similar between canine and human InvUC, especially within luminal and basal molecular subtypes. Marked transcriptomic differences were noted between early and later canine tumors, particularly within luminal subtype tumors. The deracoxib remission rate (42% CR+PR) compared very favorably to that with single-agent cyclooxygenase inhibitors in more advanced canine InvUC (17-25%), supporting the value of early intervention.

Conclusions: The study defined a novel naturally-occurring animal model to complement experimental models for early detection and intervention research in InvUC. Research incorporating the canine model is expected to lead to improved outcomes for humans, as well as pet dogs, facing bladder cancer.

Keywords: animal models; bladder cancer; cancer prevention; cancer screening; dog; early intervention; transitional cell carcinoma; urothelial carcinoma.