**7. Final remarks**

The first molecular inhibitor applied to human was the imatinib mesylate, which repress activations of KIT, platelet‐derived growth factor receptor (PDGFR), and Bcr‐Abl [45]. It was first administered to the patient of gastrointestinal stromal tumor with a mutation in the juxtamembrane domain of KIT [46]. At around the same time, KIT mutations in canine MCT were first discovered [21], suggesting the possibility that KIT inhibitors can be applied to dog MCTs. Actually, there have been several reports that show the inhibitory effects of imatinib mesylate on MCTs, especially for the tumor cells with KIT mutations in either the extracellular domain or juxtamembrane domain [22, 47]. Based on these results from basic researches, some clinicians administered imatinib mesylate to MCT‐diagnosed dogs and obtained partial response at least in some of them [47]. However, there was no rationale for the administration of imatinib mesylate to MCT‐diagnosed dogs through the clinical trials. In contrast to that, both masitinib mesylate and toceranib phosphate are approved by either the Food and Drug Administration (FDA) in the United States or European Medicines Agency based on the results from the clinical trials enrolling MCT‐diagnosed dogs [26, 48,49]. Basically, imatinib mesylate, masitinib mesylate, and toceranib phosphate are all ATP‐competitive inhibitors, and they suppress the activation of mutant KITs that require

Toceranib 86 32 (37.2%) 20 12 (60.0%) 66 20 (30.3%) Placebo 63 5 (7.9%) 9 1 (11.1%) 54 4 (7.4%) Placebo>toceranib 58 24 (41.4%) 9 7 (77.8%) 49 17 (34.7%)

The number of the enrolled patients and the proportion of CR/PR cases are indicated.

**Table 2.** Summary of a clinical trial of toceranib phosphate [26].

86 Canine Medicine - Recent Topics and Advanced Research

**All MCTs MCTs with mutant KIT MCTs without mutant KIT Cases CR + PR Cases CR + PR Cases CR + PR**

Results of clinical trials for toceranib phosphate, which is a random double‐blind trials, are summarized in **Table 2** [26]. In this trial, more than 150 MCT patients were enrolled. After the six‐week treatment, either complete response (CR) or partial response (PR) was obtained 32 in 86 (37.2%) patients in the treatment group, while the proportion of CR/PR was only 7.9% (5 in 63 patients) in the placebo group. In addition, a group treated with toceranib phosphate following placebo‐escape, which administered toceranib phosphate after the placebo treat‐ ment, responded the agent, resulting in the CR/PR in 24 cases out of 58 (41.4%). At least in this trial, significant increase in severe adverse effects (grade III or IV) was not detected. In case of mastinib mesylate, a phase III trial was carried out in France, enrolling more than 130 MCT patients. One‐year survival and two‐year survival were 62.1 and 39.8%, respectively, in the treatment group, though the ones were 36.0 and 15.0%, respectively, in the placebo

Interestingly, both agents showed antitumor effects even on MCTs expressing wild‐type KIT (**Tables 2** and **3**). Though the agents suppress the activation of other receptor tyrosine kinases

ATP binding for their activation.

group [49].

As described, molecular biological approaches to MCTs have started, and new findings are accumulating. However, some clinical researches present very limited information obtained from few cases. Therefore, clinicians should carefully collect information and evaluate data before clinical application of anticancer drugs and molecular targeting drugs to dogs with MCTs. It is dangerous to trust all data reported in few research reports or on few clinical cases. Knowledge on basic biology of mast cells will help clinicians to understand the recent molecular approaches to MCTs.
