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

Abstract

BackgroundEarly 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.MethodsSTs (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.ResultsBiopsy-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.ConclusionsThe 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.

Effects of trastuzumab emtansine on canine urothelial carcinoma cells in vitro and in vivo

“…5,49 Moreover, recent studies using genomic analyses have reported similarities of molecular features between invasive UC in humans and dogs. [50][51][52] With regard to HER2, protein overexpression has been reported in 9.2%-61.1% of human patients with MIUC. [53][54][55][56][57] Both in vitro and in vivo experiments with human UC cell lines have shown an antitumour effect of T-DM1, and the effect has been much stronger than that of trastuzumab.…”

“…Human MIUC and canine invasive UC are similar in pathology, biological behaviour, and response to chemotherapy 5,49 . Moreover, recent studies using genomic analyses have reported similarities of molecular features between invasive UC in humans and dogs 50–52 . With regard to HER2, protein overexpression has been reported in 9.2%–61.1% of human patients with MIUC 53–57 .…”

Study Design and Interim Analysis of the Cancer Lifetime Assessment Screening Study in Canines (CLASSiC): The First Prospective Cancer Screening Study in Dogs Using Next-Generation Sequencing-Based Liquid Biopsy

“…9 Early detection (whether in the preclinical period or at an earlier stage of disease) has been extensively documented to improve outcomes for many cancer types in humans 26 as well as in dogs. [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] A significant concern with all types of cancer screening is the potential for a large number of false positive results, which could lead to unnecessary procedures and expense as well as emotional distress. 5 The high PPV prospectively observed in this study provides reassurance that most OncoK9® CSD results in a high-risk cancer screening population are in fact true positives, and cancer will be found if an adequate confirmatory evaluation is performed.…”

Genome-wide analyses reveals an association between invasive urothelial carcinoma in the Shetland sheepdog and NIPAL1

“…Invasive urinary carcinoma (iUC) is the most common cancer of the urinary bladder in dogs, accounting for 90% of bladder cancers, with 40,000 newly diagnosed cases a year 12 , 13 . Naturally occurring canine iUC closely mimics human high grade MIBC in terms of age of onset, pathology, cellular and molecular features, metastatic profiles, and treatment response 14 . Approximately 50% of affected dogs will experience metastases to distant organs 15 and median survival times are typically < one year, although dogs receiving multiple sequential protocols may live beyond a year 16 , 17 .…”