Background Toceranib phosphate (TOC) could be made widely available for treating tumors in dogs if evidence shows that TOC inhibits recurrence after surgery. Objectives To investigate how postoperative adjuvant treatment with TOC modulates the tumor microenvironment (TME), by assessing effects on angiogenic activity, tumor‐infiltrating regulatory T cells (Tregs), and intratumoral hypoxia. Animals Ninety‐two client‐owned dogs were included: 28 with apocrine gland anal sac adenocarcinoma, 24 with small intestinal adenocarcinoma, 22 with lung adenocarcinoma, and 18 with renal cell carcinoma. Methods Retrospective, multicenter study comparing time to progression (TTP) between 42 dogs treated by surgery and TOC and 50 dogs treated by surgery alone. Differences were analyzed in the expression of vascular endothelial growth factor receptor‐2 (VEGFR2) and the number of Foxp3⁺ Tregs and hypoxia‐inducible factor (HIF)‐1α⁺ cells in tumor tissues sampled at the first and second (recurrence) surgeries. Results Median TTP for dogs treated by surgery and TOC (360 days) was higher than that for dogs treated by surgery alone (298 days; hazard ratio, 0.82; 95% confidence interval [CI], 0.65‐0.96; P = .02). In dogs treated by surgery and TOC, VEGFR2 expression and the number of Tregs and HIF‐1α⁺ cells were significantly lower in tissues sampled at the second surgery than in those sampled after the first surgery. In dogs treated by surgery alone, significant differences were found between samples from the 2 surgeries. Conclusions and Clinical Importance Toceranib phosphate could prove to be a useful postoperative adjuvant treatment because of its modulation of the TME.

We examined whether multidrug resistant (MDR) canine lymphoma increases gene expression for platelet-derived growth factor receptor α (PDGFRα), vascular endothelial growth factor receptor 2 (VEGFR2), and c-KIT, and whether toceranib phosphate (TOC) has potential as a treatment for MDR canine lymphoma. The clinical data showed that PDGFRα expression was higher in canine subjects with MDR T-cell lymphoma than in those with untreated T-cell lymphoma, and that c-KIT expression was greater in subjects with T-cell lymphoma than in those with B-cell lymphoma. TOC monotherapy was well tolerated without serious adverse effects, and two of the five subjects that received TOC exhibited partial responses. The data presented here could contribute to the assessment of TOC-based therapy for dogs with MDR or T-cell lymphoma.

The transcription factor hypoxia-inducible factor 1α (HIF-1α) drives metabolic reprogramming in gliomas (GLs) under hypoxic conditions, promoting glycolysis for tumor development. Evofosfamide (EVO) releases a DNA-alkylating agent within hypoxic regions, indicating that it may serve as a hypoxia-targeted therapy. The aim of this study was to investigate the glycolytic metabolism and antitumor effects of EVO in a canine GL model. Our clinical data showed that overall survival was significantly decreased in GL dog patients with higher HIF-1α expression compared to that of those with lower HIF-1α expression, and there was a positive correlation between HIF-1α and pyruvate dehydrogenase kinase 1 (PDK1) expression, suggesting that glycolytic activity under hypoxia conditions may contribute to poor outcomes in canine GL. Our glycolysis assay tests showed that the glycolytic ATP level was higher than the mitochondrial ATP level in three types of canine GL cell lines by activating the HIF-1 signal pathway under hypoxia conditions, resulting in an overall increase in total cellular ATP production. However, treatment with EVO inhibited the glycolytic ATP level in the GL cell lines under hypoxia conditions by targeting HIF-1α-positive cells, leading to decrease in total cellular ATP production. Our in vivo tests showed that EVO significantly reduced tumor development compared to controls and temozolomide in murine GL models. A metabolic analysis demonstrated that EVO effectively suppressed glycolytic metabolism by eliminating HIF-1α-positive cells, suggesting that it may restore metabolism in canine GLs. The evidence presented here supports the favorable preclinical evaluation of EVO as a potential improvement in cancer metabolism.

Background: In dogs, hepatic lymphoma is characterized by neoplastic lymphocyte infiltration into the liver. Reports on the computed tomography (CT) findings of the liver for canine hepatic lymphoma are few, with only one study of multiple liver lesions type. Objectives: The purpose of this study was to retrospectively assess the CT findings of the liver in canine diffuse hepatic lymphoma. Methods: As control, five dogs without abnormalities in the liver were included. CT data were analysed, and the following were noted: presence of edge bluntness of the liver, presence of periportal collar sign, the liver size:body weight (BW) ratio and the mean attenuation of liver lesions on pre-contrast, arterial-phase, portal-phase and equilibrium-phase post-contrast images. Results: On CT examination, edge bluntness of the liver was significantly detected in lymphoma (4/5, 80%), as opposed to the control (0/5, 0%) (p = 0.048, phi = 0.82). The periportal collar sign was detected in lymphoma (3/5, 60%), as opposed to the control (0/5, 0%) (p = 0.17, phi = 0.65). The liver size:BW ratio of lymphoma cases was significantly higher compared to that of the control cases (p = 0.0002, r = 0.92). The mean Hounsfield unit of lymphoma cases in the pre-contrast, arterial-phase, portalphase and equilibrium-phase images were significantly lower than in the control cases (p = 0.005, r = 0.81; p = 0.0003, r = 0.91; p = 0.01, r = 0.75 and p = 0.02, r = 0.71, respectively). Conclusions: Hepatic lymphoma should be a differential for a blunted and enlarged liver with hypoattenuation on CT examination.