Department of Veterinary Clinical Sciences, The Ohio State University College of Veterinary Medicine, 601 Vernon L Tharp Street, Columbus, OH 43210, USA.
BMC Vet Res. 2012 May 25;8:67. doi: 10.1186/1746-6148-8-67.
Toceranib phosphate (Palladia) has a reported objective response rate of 25% in both canine apocrine gland anal sac adenocarcinoma (AGASACA) and thyroid carcinoma (TC), with stable disease occurring in an additional 50-60% of dogs. The basis for the observed responses to toceranib is not known. The purpose of this study was to evaluate AGASACA and TC samples for the expression and activation of VEGFR2, PDGFRα, PDGFRβ, KIT and RET to assess whether dysregulation of these receptor tyrosine kinases (RTKs) may contribute to the biologic activity of toceranib.
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.
磷酸替罗尼（帕拉丁）在犬阿波基腺肛门囊腺癌（AGASACA）和甲状腺癌（TC）中报告的客观缓解率为 25%，另有 50-60%的狗疾病稳定。目前还不知道对替罗尼产生反应的基础是什么。本研究旨在评估 AGASACA 和 TC 样本中 VEGFR2、PDGFRα、PDGFRβ、KIT 和 RET 的表达和激活情况，以评估这些受体酪氨酸激酶（RTKs）的失调是否有助于替罗尼的生物学活性。
所有 AGASACA 样本中均检测到 VEGFR2、PDGFRα/β、KIT 和 RET 的 mRNA。所有 TC 样本中均检测到 VEGFR2、PDGFRα/β 和 KIT 的 mRNA，而 RET 的 mRNA 在 10/15 个样本中扩增。在阵列上未观察到 VEGFR2、PDGFRα/β 或 KIT 的磷酸化。然而，在 54%的原发性 AGASACA 和 20%的 TC 中检测到 RET 的磷酸化。VEGFR2 在 19/24 例原发性和 6/10 例转移性 AGASACA 和 6/15 例 TC 中表达。KIT 存在于 8/24 例原发性和 3/10 例转移性 AGASACA 和 9/15 例 TC 中。所有肿瘤样本均表达 PDGFRα。相比之下，PDGFRβ 表达仅见于少数肿瘤样本，但在所有肿瘤标本的基质中均可见。
替罗尼的已知靶点在 AGASAC 和 TC 中均有表达。鉴于观察到的 VEGFR 和 PDGFRα/β 的表达和 RET 的磷酸化，这些 RTKs 值得进一步研究其在 AGSACA 和 TC 生物学中的作用及其对替罗尼活性的贡献。
