Dhawan Deepika, Ramos-Vara José A, Utturkar Sagar M, Ruple Audrey, Tersey Sarah A, Nelson Jennifer B, Cooper Bruce R, Heng Hock Gan, Ostrander Elaine A, Parker Heidi G, Hahn Noah M, Adams Larry G, Fulkerson Christopher M, Childress Michael O, Bonney Patty L, Royce Christine, Fourez Lindsey M, Enstrom Alexander W, Ambrosius Lisbeth A, Knapp Deborah W
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States.
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States.
Front Oncol. 2022 Nov 11;12:1011969. doi: 10.3389/fonc.2022.1011969. eCollection 2022.
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.
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.
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 (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.
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.
早期检测和干预研究有望改善高级别肌层浸润性尿路上皮癌（InvUC）患者的预后。由于合适的高风险研究队列中的患者数量有限，相关的动物模型研究至关重要。实验动物模型往往无法充分代表人类癌症。本研究的目的是确定具有高品种相关风险的自然发生InvUC的犬类作为早期检测和干预研究相关模型的适用性。确定了筛查和早期干预的可行性，以及犬类和人类肿瘤之间以及早期和晚期犬类肿瘤之间的异同。
对120只年龄≥6岁且无泌尿系统疾病外在证据的斯塔福郡斗牛梗（STs）进行为期3年的筛查，每隔6个月进行一次体格检查、超声检查和尿液分析及沉渣检查。对筛查试验呈阳性的犬进行膀胱镜活检。确定通过筛查检测到的“早期”癌症的病理、临床和分子特征。将早期肿瘤的转录组特征与已发表的人类InvUC研究结果进行比较，并与患有血尿和排尿功能障碍典型表现的STs中更晚期的“晚期”犬类肿瘤进行比较。对通过筛查检测出患有癌症的犬进行口服环氧化酶抑制剂德拉考昔的早期干预试验。
在120只STs中，32只（27%）经活检确诊患有膀胱癌，包括InvUC（n = 29，3例起始为发育异常）、1级非浸润性癌（n = 2）和癌（n = 1）。包括可药物作用靶点如表皮生长因子受体（EGFR）和磷脂酰肌醇-蛋白激酶B-哺乳动物雷帕霉素靶蛋白（PI3K-AKT-mTOR）通路在内的转录组特征在犬类和人类InvUC之间非常相似，尤其是在管腔和基底分子亚型内。在早期和晚期犬类肿瘤之间观察到明显的转录组差异，特别是在管腔亚型肿瘤内。德拉考昔的缓解率（42%完全缓解+部分缓解）与更晚期犬类InvUC中单药环氧化酶抑制剂的缓解率（17 - 25%）相比非常有利，支持早期干预的价值。
该研究定义了一种新型的自然发生动物模型，以补充用于InvUC早期检测和干预研究的实验模型。纳入犬类模型的研究有望改善面临膀胱癌的人类以及宠物犬的预后。
