- Email: [email protected]
Receptor tyrosine kinase KIT: Prognostic and therapeutic involvement in canine mast cell tumours
Accepted Manuscript Title: Receptor tyrosine kinase KIT: prognostic and therapeutic involvement in canine mast cell tumours Author: Yoshinori Takeuchi, Makoto Bonkobara PII: DOI: Reference:
S1090-0233(15)00303-2 http://dx.doi.org/doi:10.1016/j.tvjl.2015.07.012 YTVJL 4561
To appear in:
The Veterinary Journal
Please cite this article as: Yoshinori Takeuchi, Makoto Bonkobara, Receptor tyrosine kinase KIT: prognostic and therapeutic involvement in canine mast cell tumours, The Veterinary Journal (2015), http://dx.doi.org/doi:10.1016/j.tvjl.2015.07.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Guest Editorial
2 3
Receptor tyrosine kinase KIT: Prognostic and therapeutic involvement in canine
4
mast cell tumours
5 6
A recent article by Dr Rui Gil da Costa, from the Universidade do Porto, Portugal,
7
published in The Veterinary Journal, reviewed the scientific literature on the involvement
8
of the receptor tyrosine kinase (RTK) KIT in canine mast cell tumours (MCTs) and
9
related background information up to 2014 (Gil da Costa, 2015). This comprehensive
10
review article is highly valuable for veterinary oncologists who need to keep up to date
11
with cutting edge research, to identify gaps in current knowledge and to focus on areas
12
for future research.
13 14
Gil da Costa (2015) first introduces predictive indicators for the prognosis of
15
canine MCTs, such as histological grading, genetic status and protein expression;
16
mutation of KIT is the most important prognostic factor of all of these markers. Although
17
KIT is expressed in normal mast cells and plays an important role in mast cell activation,
18
some KIT mutations induce constitutive autophosphorylation, which can promote
19
uncontrolled cell proliferation and survival of tumour cells. An internal tandem
20
duplication (ITD) within exon 11 of KIT is associated with a shorter survival time for
21
dogs with MCTs (Gil da Costa, 2015). However, this mutation was not observed in ~70%
22
of 46 canine cutaneous MCTs on examination of the open reading frame of KIT mRNA
23
(Takeuchi et al., 2013). Further research is required to determine whether the KIT
Page 1 of 5
24
mutation contributes to the pathobiology of canine MCT by acting as a cancer initiator or
25
promoter.
26 27
Gil da Costa (2015) also describes the significant correlation between KIT
28
expression patterns and cell proliferation indices, such as Ki-67 and argyrophilic
29
nucleolar organiser region (AgNOR). It is suggested that the Kiupel histopathological
30
grading system for canine MCT, which largely relies on mitotic index and cytological
31
abnormalities (Kiupel et al., 2011), can be adapted to the aberrant KIT expression pattern.
32
The Kiupel histopathological grade is strongly associated with survival time and the
33
presence of an ITD within exon 11 of KIT (Takeuchi et al., 2013). It is expected that a
34
more suitable predictive panel for canine MCT, which combines the Kiupel grading
35
system, KIT expression pattern and KIT mutations, will be established in the near future.
36 37
RTK inhibitors have emerged as anticancer therapeutic agents and have been used
38
widely for treatment of various human tumours. Two RTK inhibitors (toceranib and
39
masitinib) exhibit favourable treatment outcomes against canine MCT; the efficacy of
40
both RTK inhibitors has been evaluated in placebo-controlled randomised trials (Hahn et
41
al., 2008; London et al., 2009). In addition to these drugs, another RTK inhibitor,
42
imatinib, which was originally developed as a therapeutic agent for human chronic
43
myeloid leukaemia, also exhibits efficacy against canine MCTs (Bonkobara, 2015).
44
These three RTK inhibitors can inhibit the kinase activity of KIT and, as a consequence,
45
cases of canine MCT with KIT mutations are more likely to respond to treatment with
46
these drugs than those without mutations (Bonkobara, 2015; Gil da Costa, 2015).
Page 2 of 5
47 48
However, the overall response rates to monotherapy with RTK inhibitors for
49
canine MCTs were only 42-48% (Hahn et al., 2008; London et al., 2009). In addition,
50
some dogs with MCTs eventually develop resistance and relapse, even after remission
51
following treatment with RTK inhibitors. Novel therapeutic schemes to treat canine
52
MCTs, such as new RTK inhibitors or combination therapy with traditional cytotoxic
53
agents, have been examined to overcome resistance (Gil da Costa, 2015). Our previous
54
study indicated that masitinib, imatinib and axitinib inhibit proliferation of a canine MCT
55
cell line with a KIT mutation (Takeuchi et al., 2012). The RTK inhibitor axitinib has
56
recently been approved by the US Food and Drug Administration, and the European
57
Medicines Agency, for the treatment of advanced human renal cell carcinoma (Zakharia
58
et al., 2015). Axitinib thus may be a candidate for therapy of canine MCTs.
59 60
Gil da Costa (2015) rightly mentions the adverse effects of administration of RTK
61
inhibitors as an important issue that should not be ignored. In previous studies, relatively
62
moderate adverse effects were associated with toceranib, masitinib or imatinib
63
monotherapy (Hahn et al., 2008; London et al., 2009; Bonkobara, 2015). However, it is
64
important to be aware of drug interactions when using combination therapy with RTK
65
inhibitors and other anticancer agents. Furthermore, some rare life-threatening side
66
effects of RTK inhibitors, such as acute renal failure or prolonged Q-T interval have been
67
reported in human patients (Shah et al., 2013; Abbas et al., 2015). Since these adverse
68
effects are difficult to distinguish from the clinical signs associated with tumour
Page 3 of 5
69
progression, a large scale pharmacoepidemiological approach focused on toxicity is
70
necessary to confirm the risk profile of RTK inhibitors in veterinary medicine.
71 72
Gil da Costa (2015) suggests that the development and application of KIT
73
inhibitors to treat canine MCTs is an excellent example of translational research where
74
laboratory research translates into the development of new clinical practice in the
75
veterinary field. Even if the candidate therapeutic target is identified, large scale clinical
76
trials using novel drugs are difficult to conduct because of the high costs involved.
77
Conversely, Gil da Costa (2015) reports that the application of masitinib for canine
78
MCTs has been treated as a spontaneous animal model of human mast cell neoplasms.
79
We believe that the development of therapeutics in human and veterinary medicine will
80
be advanced concurrently if veterinary patients are perceived to have a role as clinical
81
animal models for analogous human diseases.
82 83 84 85 86 87 88 89 90 91 92 93
Yoshinori Takeuchi Office of Medical Informatics and Epidemiology Pharmaceuticals and Medical Devices Agency 3-3-2, Kasumigaseki, Chiyoda-ku, Tokyo 100-0013, Japan E-mail address: [email protected] Makoto Bonkobara Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
94
References
95 96 97
Abbas, A., Mirza, M.M., Ganti, A.K., Tendulkar, K., 2015. Renal toxicities of targeted therapies. Targeted Oncology doi: 10.1007/s11523-015-0368-7.
Page 4 of 5
98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139
Bonkobara, M., 2015. Dysregulation of tyrosine kinases and use of imatinib in small animal practice. The Veterinary Journal doi: 10.1016/j.tvjl.2014.12.015. Gil da Costa, R.M., 2015. C-kit as a prognostic and therapeutic marker in canine cutaneous mast cell tumours: From laboratory to clinic. The Veterinary Journal 205, 5-10. Hahn, K.A., Ogilvie, G., Rusk, T., Devauchelle, P., Leblanc, A., Legendre, A., Powers, B., Leventhal, P.S., Kinet, J.P., Palmerini, F., et al., 2008. Masitinib is safe and effective for the treatment of canine mast cell tumors. Journal of Veterinary Internal Medicine 22, 1301-1309. Kiupel, M., Webster, J.D., Bailey, K.L., Best, S., DeLay, J., Detrisac, C.J., Fitzgerald, S.D., Gamble, D., Ginn, P.E., Goldschmidt, M.H., et al., 2011. Proposal of a 2tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior. Veterinary Pathology 48, 147-155. London, C.A., Malpas, P.B., Wood-Follis, S.L., Boucher, J.F., Rusk, A.W., Rosenberg, M.P., Henry, C.J., Mitchener, K.L., Klein, M.K., Hintermeister, J.G., et al., 2009. Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clinical Cancer Research 15, 3856-3865. Shah, R.R., Morganroth, J., Shah, D.R., 2013. Cardiovascular safety of tyrosine kinase inhibitors: With a special focus on cardiac repolarisation (QT interval). Drug Safety 36, 295-316. Takeuchi, Y., Fujino, Y., Fukushima, K., Watanabe, M., Nakagawa, T., Ohno, K., Sasaki, N., Sugano, S., Tsujimoto, H., 2012. Biological effect of tyrosine kinase inhibitors on three canine mast cell tumor cell lines with various KIT statuses. Journal of Veterinary Pharmacology and Therapeutics 35, 97-104. Takeuchi, Y., Fujino, Y., Watanabe, M., Takahashi, M., Nakagawa, T., Takeuchi, A., Bonkobara, M., Kobayashi, T., Ohno, K., Uchida, K., et al., 2013. Validation of the prognostic value of histopathological grading or c-kit mutation in canine cutaneous mast cell tumours: A retrospective cohort study. The Veterinary Journal 196, 492-498. Zakharia, Y., Zakharia, K., Rixe, O., 2015. Axitinib: From preclinical development to future clinical perspectives in renal cell carcinoma. Expert Opinion on Drug Discovery doi: 10.1517/17460441.2015.1045411.
Page 5 of 5
S1090-0233(15)00303-2 http://dx.doi.org/doi:10.1016/j.tvjl.2015.07.012 YTVJL 4561
To appear in:
The Veterinary Journal
Please cite this article as: Yoshinori Takeuchi, Makoto Bonkobara, Receptor tyrosine kinase KIT: prognostic and therapeutic involvement in canine mast cell tumours, The Veterinary Journal (2015), http://dx.doi.org/doi:10.1016/j.tvjl.2015.07.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Guest Editorial
2 3
Receptor tyrosine kinase KIT: Prognostic and therapeutic involvement in canine
4
mast cell tumours
5 6
A recent article by Dr Rui Gil da Costa, from the Universidade do Porto, Portugal,
7
published in The Veterinary Journal, reviewed the scientific literature on the involvement
8
of the receptor tyrosine kinase (RTK) KIT in canine mast cell tumours (MCTs) and
9
related background information up to 2014 (Gil da Costa, 2015). This comprehensive
10
review article is highly valuable for veterinary oncologists who need to keep up to date
11
with cutting edge research, to identify gaps in current knowledge and to focus on areas
12
for future research.
13 14
Gil da Costa (2015) first introduces predictive indicators for the prognosis of
15
canine MCTs, such as histological grading, genetic status and protein expression;
16
mutation of KIT is the most important prognostic factor of all of these markers. Although
17
KIT is expressed in normal mast cells and plays an important role in mast cell activation,
18
some KIT mutations induce constitutive autophosphorylation, which can promote
19
uncontrolled cell proliferation and survival of tumour cells. An internal tandem
20
duplication (ITD) within exon 11 of KIT is associated with a shorter survival time for
21
dogs with MCTs (Gil da Costa, 2015). However, this mutation was not observed in ~70%
22
of 46 canine cutaneous MCTs on examination of the open reading frame of KIT mRNA
23
(Takeuchi et al., 2013). Further research is required to determine whether the KIT
Page 1 of 5
24
mutation contributes to the pathobiology of canine MCT by acting as a cancer initiator or
25
promoter.
26 27
Gil da Costa (2015) also describes the significant correlation between KIT
28
expression patterns and cell proliferation indices, such as Ki-67 and argyrophilic
29
nucleolar organiser region (AgNOR). It is suggested that the Kiupel histopathological
30
grading system for canine MCT, which largely relies on mitotic index and cytological
31
abnormalities (Kiupel et al., 2011), can be adapted to the aberrant KIT expression pattern.
32
The Kiupel histopathological grade is strongly associated with survival time and the
33
presence of an ITD within exon 11 of KIT (Takeuchi et al., 2013). It is expected that a
34
more suitable predictive panel for canine MCT, which combines the Kiupel grading
35
system, KIT expression pattern and KIT mutations, will be established in the near future.
36 37
RTK inhibitors have emerged as anticancer therapeutic agents and have been used
38
widely for treatment of various human tumours. Two RTK inhibitors (toceranib and
39
masitinib) exhibit favourable treatment outcomes against canine MCT; the efficacy of
40
both RTK inhibitors has been evaluated in placebo-controlled randomised trials (Hahn et
41
al., 2008; London et al., 2009). In addition to these drugs, another RTK inhibitor,
42
imatinib, which was originally developed as a therapeutic agent for human chronic
43
myeloid leukaemia, also exhibits efficacy against canine MCTs (Bonkobara, 2015).
44
These three RTK inhibitors can inhibit the kinase activity of KIT and, as a consequence,
45
cases of canine MCT with KIT mutations are more likely to respond to treatment with
46
these drugs than those without mutations (Bonkobara, 2015; Gil da Costa, 2015).
Page 2 of 5
47 48
However, the overall response rates to monotherapy with RTK inhibitors for
49
canine MCTs were only 42-48% (Hahn et al., 2008; London et al., 2009). In addition,
50
some dogs with MCTs eventually develop resistance and relapse, even after remission
51
following treatment with RTK inhibitors. Novel therapeutic schemes to treat canine
52
MCTs, such as new RTK inhibitors or combination therapy with traditional cytotoxic
53
agents, have been examined to overcome resistance (Gil da Costa, 2015). Our previous
54
study indicated that masitinib, imatinib and axitinib inhibit proliferation of a canine MCT
55
cell line with a KIT mutation (Takeuchi et al., 2012). The RTK inhibitor axitinib has
56
recently been approved by the US Food and Drug Administration, and the European
57
Medicines Agency, for the treatment of advanced human renal cell carcinoma (Zakharia
58
et al., 2015). Axitinib thus may be a candidate for therapy of canine MCTs.
59 60
Gil da Costa (2015) rightly mentions the adverse effects of administration of RTK
61
inhibitors as an important issue that should not be ignored. In previous studies, relatively
62
moderate adverse effects were associated with toceranib, masitinib or imatinib
63
monotherapy (Hahn et al., 2008; London et al., 2009; Bonkobara, 2015). However, it is
64
important to be aware of drug interactions when using combination therapy with RTK
65
inhibitors and other anticancer agents. Furthermore, some rare life-threatening side
66
effects of RTK inhibitors, such as acute renal failure or prolonged Q-T interval have been
67
reported in human patients (Shah et al., 2013; Abbas et al., 2015). Since these adverse
68
effects are difficult to distinguish from the clinical signs associated with tumour
Page 3 of 5
69
progression, a large scale pharmacoepidemiological approach focused on toxicity is
70
necessary to confirm the risk profile of RTK inhibitors in veterinary medicine.
71 72
Gil da Costa (2015) suggests that the development and application of KIT
73
inhibitors to treat canine MCTs is an excellent example of translational research where
74
laboratory research translates into the development of new clinical practice in the
75
veterinary field. Even if the candidate therapeutic target is identified, large scale clinical
76
trials using novel drugs are difficult to conduct because of the high costs involved.
77
Conversely, Gil da Costa (2015) reports that the application of masitinib for canine
78
MCTs has been treated as a spontaneous animal model of human mast cell neoplasms.
79
We believe that the development of therapeutics in human and veterinary medicine will
80
be advanced concurrently if veterinary patients are perceived to have a role as clinical
81
animal models for analogous human diseases.
82 83 84 85 86 87 88 89 90 91 92 93
Yoshinori Takeuchi Office of Medical Informatics and Epidemiology Pharmaceuticals and Medical Devices Agency 3-3-2, Kasumigaseki, Chiyoda-ku, Tokyo 100-0013, Japan E-mail address: [email protected] Makoto Bonkobara Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
94
References
95 96 97
Abbas, A., Mirza, M.M., Ganti, A.K., Tendulkar, K., 2015. Renal toxicities of targeted therapies. Targeted Oncology doi: 10.1007/s11523-015-0368-7.
Page 4 of 5
98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139
Bonkobara, M., 2015. Dysregulation of tyrosine kinases and use of imatinib in small animal practice. The Veterinary Journal doi: 10.1016/j.tvjl.2014.12.015. Gil da Costa, R.M., 2015. C-kit as a prognostic and therapeutic marker in canine cutaneous mast cell tumours: From laboratory to clinic. The Veterinary Journal 205, 5-10. Hahn, K.A., Ogilvie, G., Rusk, T., Devauchelle, P., Leblanc, A., Legendre, A., Powers, B., Leventhal, P.S., Kinet, J.P., Palmerini, F., et al., 2008. Masitinib is safe and effective for the treatment of canine mast cell tumors. Journal of Veterinary Internal Medicine 22, 1301-1309. Kiupel, M., Webster, J.D., Bailey, K.L., Best, S., DeLay, J., Detrisac, C.J., Fitzgerald, S.D., Gamble, D., Ginn, P.E., Goldschmidt, M.H., et al., 2011. Proposal of a 2tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior. Veterinary Pathology 48, 147-155. London, C.A., Malpas, P.B., Wood-Follis, S.L., Boucher, J.F., Rusk, A.W., Rosenberg, M.P., Henry, C.J., Mitchener, K.L., Klein, M.K., Hintermeister, J.G., et al., 2009. Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clinical Cancer Research 15, 3856-3865. Shah, R.R., Morganroth, J., Shah, D.R., 2013. Cardiovascular safety of tyrosine kinase inhibitors: With a special focus on cardiac repolarisation (QT interval). Drug Safety 36, 295-316. Takeuchi, Y., Fujino, Y., Fukushima, K., Watanabe, M., Nakagawa, T., Ohno, K., Sasaki, N., Sugano, S., Tsujimoto, H., 2012. Biological effect of tyrosine kinase inhibitors on three canine mast cell tumor cell lines with various KIT statuses. Journal of Veterinary Pharmacology and Therapeutics 35, 97-104. Takeuchi, Y., Fujino, Y., Watanabe, M., Takahashi, M., Nakagawa, T., Takeuchi, A., Bonkobara, M., Kobayashi, T., Ohno, K., Uchida, K., et al., 2013. Validation of the prognostic value of histopathological grading or c-kit mutation in canine cutaneous mast cell tumours: A retrospective cohort study. The Veterinary Journal 196, 492-498. Zakharia, Y., Zakharia, K., Rixe, O., 2015. Axitinib: From preclinical development to future clinical perspectives in renal cell carcinoma. Expert Opinion on Drug Discovery doi: 10.1517/17460441.2015.1045411.
Page 5 of 5