Evaluation of expression and function of vascular endothelial growth factor receptor 2, platelet derived growth factor receptors-alpha and -beta, KIT, and RET in canine apocrine gland anal sac adenocarcinoma and thyroid carcinoma

mRNA for VEGFR2, PDGFRα/β, KIT and RET was detected in all AGASACA samples. mRNA for VEGFR2, PDGFRα/β, and KIT was detected in all TC samples, while mRNA for RET was amplified in 10/15 samples. No phosphorylation of VEGFR2, PDGFRα/β, or KIT was observed on the arrays. However, phosphorylation of RET was detected in 54% of the primary AGASACA and 20% of TC. VEGFR2 was expressed in 19/24 primary and 6/10 metastatic AGASACA and 6/15 TC samples. KIT was present in 8/24 primary and 3/10 metastatic AGASACA and 9/15 TC samples. PDGFRα expression was noted in all tumor samples. In contrast PDGFRβ expression was found in only a few tumor samples but was evident in the stroma of all tumor specimens.Known targets of toceranib are expressed in both AGASAC and TC. Given the observed expression of VEGFR and PDGFRα/β and phosphorylation of RET, these RTKs merit investigation as to their roles in the biology of AGSACA and TC and their contribution to toceranib’s activity.Toceranib phosphate (Palladia？; Pfizer Animal Health, Madison, NJ, USA) is an oral oxindole multi-targeted receptor tyrosine kinase (RTK) inhibitor (TKI) that blocks the activity of VEGFR2, PDGFRα,/β, FMS-like tyrosine kinase 3 (FLT-3), stem cell factor receptor (KIT), and colony stimulating factor receptor (CSFR1) [1]. It was approved for the treatment of canine mast cell tumors (MCTs) based on a single agent response rate of approximately 43% in dogs with recurrent or non-resectable grade 2 or 3 MCTs [2]. Toceranib also exhibited activity against multiple tumor types in the original phase 1 study, suggesting that the action of toceranib against receptors other than KIT may play a role in the responses observed in solid tumors [3]. In support of this, toceranib’s kinome mirrors that of sunitinib (Sutent？, Pfizer Inc, New York, NY), a very closely related multi-targeted TKI that has demonstrated activity against renal cell carcinoma, gastrointestinal stromal tumors, thyroid carcinomas, and pancreatic neuroendocrine