Molecular-Targeting Therapy With Imatinib in Mast Cell Tumors
World Small Animal Veterinary Association World Congress Proceedings, 2013
Makoto Bonkobara, DVM, PhD
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan

Targeted therapy is a new therapeutic approach for canine and feline mast cell tumors (MCTs). Imatinib, also known as Gleevec®, is a small-molecule tyrosine kinase inhibitor. Imatinib competes with adenosine triphosphate (ATP) for the ATP binding site of protein-tyrosine kinase and prevents downstream signaling. Therefore, it possesses potent therapeutic activity against human tumors driven by constitutively phosphorylated protein-tyrosine kinases, such as Bcr-Abl in Philadelphia-positive chronic myeloid leukemia, and mutated KIT. Mutation in the corresponding c-kit gene leads to gastrointestinal stromal cell tumors.

Imatinib has clinical activity against MCTs in dogs and cats. In dogs, imatinib has been shown to be an active agent in the treatment of certain cases of canine MCT, achieving complete response (CR) or partial response (PR) (10 out of 21 dogs) within 7 days (Isotani et al. 2008) (Figure 1). Five of the 21 dogs possessed demonstrable c-kit internal tandem duplication (ITD) mutations of exon 11 within tumor cells, and all of the dogs with an ITD mutation responded to imatinib. This suggests the importance of the c-kit exon 11 ITD mutation as an imatinib target. However, in addition to ITD-positive MCT cases some dogs with ITD-negative MCTs responded to imatinib in a similar manner to ITD-positive MCTs (Figure 1). This indicates that aberrant phosphorylation of KIT caused by c-kit exon 11 ITD mutations might not be solely attributable to the clinical response to imatinib in dogs with MCTs. Recently, clinical responses to imatinib have been reported in two dogs with MCTs that carried a c-kit exon 8 ITD mutation (Kobayashi et al. 2012) and exon 9 point mutation (Yamada et al. 20011), respectively. In addition to the exon 11 ITD mutation these mutations could be valuable therapeutic targets for imatinib in canine MCTs.

Figure 1
Figure 1

Changes in tumor size after treatment with imatinib. Changes in the tumor volume (n = 21) are presented as percentages of the initial volume. Dotted and solid lines represent response of tumors with and without c-kit internal tandem duplication mutation, respectively.
 

In a clinical study of 10 cats with MCTs a beneficial response to imatinib was observed in 7/8 cats that had a mutation in the fifth IgD of KIT in tumor cells (Isotani et al. 2010). The status of the c-kit mutation and the response to imatinib in 10 cases of feline MCTs is shown in Table 1. Among the 10 cats enrolled, eight had a c-kit mutation in exon 8 (5 cats) or exon 9 (3 cats). The MCTs of two cats had no detectable mutation. Of the eight cats that had a mutation in c-kit objective responses to imatinib therapy were achieved in seven cats, including PR or CR after 2 to 3 weeks of treatment. One cat maintained stable disease (SD) during the treatment period (13 weeks). Mutations in the fifth IgD of KIT appear to be sensitive to imatinib in feline MCTs. Of two cats that had no detectable c-kit mutation, one cat achieved PR after 3 weeks of treatment with imatinib.

A target in a presently undefined novel oncogenic kinase could underlie the response of MCTs in this cat.

Table 1. Mutation status of c-kit and clinical responses to imatinib in cats with mast cell tumors

Case no.

Affected region/mastocytoma

Mutation (type)

Best response/
time to response (wks)

1

Skin (S)/-

Exon 8 (c.1244_1255dup)

PR/3

2

Skin (M), spleen, liver/+

Exon 8 (c.1244_1255dup)

PR/3

3

Skin (M)/-

Exon 8 (c.1244_1255dup)

PR/3

4

Spleen, liver/+

Exon 8 (c.1244_1255dup)

CR/2

5

Spleen, liver/+

Exon 8 (c.1244_1255dup)

SD

6

Skin (M)/-

Exon 9 (c.1430G>T)

PR/2

7

Skin (S)/-

Exon 9 (c.1430G>T)

PR/2

8

Skin (S)/-

Exon 9 (c.1517_1518delinsTT)

PR/3

9

Skin (M), spleen, liver/+

None

PR/3

10

Skin (S)/+

None

SD

(S), solitary lesion; (M), multiple lesions; CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease
Table modified from: Isotani M, et al. Br J Haematol. 2010;148(1):144–153.

In this session, I will describe the clinical aspects of targeted therapy using imatinib in canine and feline MCTs. I will also touch on the side effects of imatinib in dogs and cats.

References

1.  Isotani M, Ishida N, Tominaga M, et al. Effect of tyrosine kinase inhibition by imatinib mesylate on mast cell tumors in dogs. J Vet Intern Med. 2008;22:985–988.

2.  Kobayashi M, Sugisaki O, Ishii N, et al. Canine intestinal mast cell tumor with c-kit exon 8 mutation responsive to imatinib therapy. Vet J. 2012;193:264–267.

3.  Yamada O, Kobayashi M, Sugisaki O, et al. Imatinib elicited a favorable response in a dog with a mast cell tumor carrying a c-kit c.1523A>T mutation via suppression of constitutive KIT activation. Vet Immunol Immunopathol. 2011;142:101–106.

4.  Isotani M, Yamada O, Lachowicz JL, et al. Mutations in the fifth immunoglobulin-like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumours. Br J Haematol. 2010;148:144–153.

  

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Makoto Bonkobara, DVM, PhD
Department of Veterinary Clinical Pathology
Nippon Veterinary and Life Science University
Musashino-shi, Tokyo, Japan


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