The Veterinary Journal 205 (2015) 122–123
Contents lists available at ScienceDirect
The Veterinary Journal j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t v j l
Guest Editorial
Small molecule kinase inhibitors in veterinary oncology
Cancer is a heterogeneous collection of diseases characterized by the following hallmarks: uncontrolled proliferation, resistance to cell death, replicative immortality, resistance to growth suppressive signaling, angiogenesis, and invasion and metastases (Hanahan and Weinberg, 2011). Cancer is due to a combination of mutations, chromosomal rearrangements or aberrations, and epigenetic changes that affect genes, and therefore proteins, that regulate these hallmark phenotypes (Hanahan and Weinberg, 2011; Tsai and Nussinov, 2013; Vogelstein et al., 2013). Recent genomic advances have allowed for the characterization of entire cancer genomes. These efforts have identified an average of 33–66 somatic mutations in common human tumors including breast, colon, and pancreatic cancer (Vogelstein et al., 2013). The goal of targeted therapy is to treat patients through modulation of specific molecular events associated with a patient’s cancer. Targeted therapy may be based on known driver gene mutations, but may also work through modulation of the tumor microenvironment or the immune system. At first glance, targeted therapy appears to be a daunting and potentially unsurmountable task in the presence of 33–66 somatic mutations in a single tumor. However, deeper evaluations of cancer genomes have revealed that there are far fewer driver mutations that are truly responsible for the progression of a given cancer with the remaining mutations merely being passengers. Additionally, these driver genes are members of at least one of 12 signaling pathways (Vogelstein et al., 2013). In the current Special Issue of The Veterinary Journal, Professor Robert Klopfleisch of the Freie Universität Berlin delves deeper into the concept of personalized medicine and the impact that -omic technologies, including genomics, proteomics, and transcriptomics, have played in understanding of cancer biology (Klopfleisch, 2015). Although veterinary medicine is lagging behind advances in human medicine, Klopfleisch provides numerous examples of how his laboratory and others have begun to use transcriptional profiling, proteomic profiling, and other emerging technologies to understand veterinary cancers, to identify prognostic markers or gene expression profiles, and to advance disease detection and evaluations of disease progression (Klopfleisch, 2015). Further optimism for targeted therapies is provided in the concept of oncogene addiction, which is a cancer’s dependency on one or a few genes for continued progression and survival (Weinstein and Joe, 2008; Tsai and Nussinov, 2013). In human medicine, evidence for oncogene addiction has been seen in clinical responses to small molecule inhibitors that target specific mutated or fusion proteins including inhibition of the BCR–ABL protein in chronic myelogenous leukemia, mutant EGFR or ALK fusions in lung cancer, and mutant BRAF in melanoma. A notable theme of the above examples http://dx.doi.org/10.1016/j.tvjl.2015.01.026 1090-0233/© 2015 Elsevier Ltd. All rights reserved.
of small molecule inhibitors is that they all target kinases. With 518 family members, kinases and their phospho-transfer reactions are critical to most signaling pathways and therefore most basic functions of the cell. Targeting kinases’ ATP binding sites allows for somewhat selective kinase inhibition and is relatively well tolerated. Together, the critical role kinases play in cancer progression and the ability to safely and selectively inhibit many kinases has made them a key family of oncology therapeutic targets (Zhang et al., 2009). In the current special issue of The Veterinary Journal, several manuscripts describe recent advances in veterinary oncology to identify, characterize, and target kinases driving canine and feline cancers. With the identification of KIT mutations in approximately 15–30% of canine mast cell tumors (MCTs) (Webster et al., 2006; Letard et al., 2008), the KIT inhibitors toceranib, masitinib, and imatinib have provided the first examples of small molecule kinase inhibitors in veterinary oncology (London, 2014). Toceranib and masitinib have received approval or conditional approval for the treatment of canine MCT from the US Food and Drug Administration (FDA). Mounting evidence from clinical trials suggests that these drugs have increased efficacy in dogs with activating KIT mutations; however, therapeutic benefits have been observed in dogs without these mutations, either through inhibition of related kinases or inhibition of KIT that has increased activation through non-mutational mechanisms (London, 2014). Imitinib is a tyrosine kinase inhibitor that was originally developed to target the BCR–ABL fusion protein in chronic myelogenous leukemia, but also inhibits the receptor tyrosine kinases KIT and platelet-derived growth factor (Capdeville et al., 2002). In this issue of The Veterinary Journal, Dr. Makoto Bonkobara from the Nippon Veterinary and Life Science University describes the use of imatinib to treat both canine and feline MCTs, but also addresses additional studies that have evaluated imatinib in other canine and feline neoplastic and non-neoplastic diseases (Bonkobara, 2015). The use of imatinib in canine and feline MCTs is based on the known role KIT mutations play in MCT progression (Bonkobara, 2015). Similarly, based on previous evidence of decreased Wnt signaling in canine melanoma (Chon et al., 2013) and evidence of an association between Wnt signaling and decreased proliferation in human melanoma (Chien et al., 2009), Chon et al. (2014) evaluated 6-bromoindirubin-3’oxime (BIO), a glycogen synthase kinase-3 beta inhibitor, in canine melanoma cell lines (Chon et al., 2014). This work is a great example of the integration of human and veterinary oncology knowledge to test a therapeutic hypothesis and to develop novel therapeutic strategies. Identification of shared molecular phenotypes of human and veterinary diseases may best enable the identification of targeted therapies that can benefit both species.
Guest Editorial/The Veterinary Journal 205 (2015) 122–123
In contrast to the a priori, hypothesis-driven approaches described above, another manuscript from the current issue of The Veterinary Journal used a kinase inhibitor library screen to identify potential osteosarcoma inhibitors (Mauchle et al., 2015). This screen identified four small molecule inhibitors that inhibit protein kinase C, the IκB kinase complex, epidermal growth factor receptor, adenosine kinase, and multiple serine/threonine kinases. As such, this study identified multiple potential therapeutic targets to explore for treating canine osteosarcoma. However, this study also demonstrated variability in the cell lines’ responses to the inhibitors (Mauchle et al., 2015), highlighting the importance to understand the biology of a given cancer prior to treatment and the importance of biomarkers to identify the activation of the targeted pathway in the cancer. We are only beginning to understand the molecular mechanisms of veterinary cancers and little is known about the molecular drivers of many canine and feline cancers. Identification of molecular targets and biomarkers associated with these targets will be essential to fully harness the power of kinase inhibitors in veterinary oncology. Dr. Lorella Maniscalco and her colleagues at the University of Turin investigated the role of insulin-like growth factor-1 receptor (IGFR-1) in canine osteosarcoma (Maniscalco et al., 2014). In this study, they showed that IGFR-1 is expressed in canine osteosarcoma, provided epidemiological data suggesting that increased IGFR-1 expression is associated with decreased survival, and demonstrated that IGFR-1 inhibition resulted in increased apoptosis in vitro (Maniscalco et al., 2014). The identification and characterization of targets require a combined body of evidence including epidemiological, in vitro, and in vivo data with the final test of the therapeutic hypothesis in well-designed and powered clinical trials (Heller, 2015; Thamm and Vail, 2015). It is anticipated that small molecule kinase inhibitors will play an increasingly important role in veterinary oncology. However, the foundation of this transition rests on the further understanding of the molecular biology of veterinary cancers (Klopfleisch, 2015), the identification of therapeutic targets with relevant biomarkers, and the utilization of rigorous clinical trials to validate therapeutic hypotheses as has been pointed out by two of the review articles in the current issue of The Veterinary Journal (Heller, 2015; Thamm and Vail, 2015). The articles in this Special Issue of The Veterinary Journal on Veterinary Oncology highlight the strides being made to push forward the field of veterinary oncology and provide an optimistic perspective of the future. Joshua D. Webster Department of Pathology, Genentech, Inc., South San Francisco, CA 90480, USA E-mail address: [email protected]
123
References Bonkobara, M., 2015. Dysregulation of tyrosine kinases and use of imatinib in small animal practice. The Veterinary Journal doi.org/10.1016/j.tvjl.2014.12.015. Capdeville, R., Buchdunger, E., Zimmermann, J., Matter, A., 2002. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Reviews Drug Discovery 1, 493–502. Chien, A.J., Moore, E.C., Lonsdorf, A.S., Kulikauskas, R.M., Rothberg, B.G., Berger, A.J., Major, M.B., Hwang, S.T., Rimm, D.L., Moon, R.T., 2009. Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proceedings of the National Academy of Sciences of the United States of America 106, 1193–1198. Chon, E., Thompson, V., Schmid, S., Stein, T.J., 2013. Activation of the canonical Wnt/beta-catenin signalling pathway is rare in canine malignant melanoma tissue and cell lines. Journal of Comparative Pathology 148, 178–187. Chon, E., Flanagan, B., de Sa Rodrigues, L.C., Piskun, C., Stein, T.J., 2014. 6-Bromoindirubin 3’oxime (BIO) decreases proliferation and migration of canine melanoma cell lines. The Veterinary Journal doi.org/10.1016/j.tvjl.2014.07.012. Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: The next generation. Cell 144, 646–674. Heller, J., 2015. Epidemiological and statistical considerations for interpreting and communicating oncological clinical trials. The Veterinary Journal in press. Klopfleisch, R., 2015. Personalized medicine in veterinary oncology: One to cure just one. The Veterinary Journal doi.org/10.1016/j.tvjl.2015.01.004. Letard, S., Yang, Y., Hanssens, K., Palmerini, F., Leventhal, P.S., Guery, S., Moussy, A., Kinet, J.P., Hermine, O., Dubreuil, P., 2008. Gain-of-function mutations in the extracellular domain of KIT are common in canine mast cell tumors. Molecular Cancer Research 6, 1137–1145. London, C.A., 2014. Small molecule inhibitors in veterinary oncology practice. Veterinary Clinics of North America Small Animal Practice 44, 893–908. Maniscalco, L., Iussich, S., Morello, E., Martano, M., Gattino, F., Miretti, S., Biolatti, B., Accornero, P., Martignani, E., Sanchez-Cespedes, R., et al., 2014. Increased expression of insulin-like growth factor-1 receptor is correlated with worse survival in canine appendicular osteosarcoma. The Veterinary Journal doi.org/ 10.1016/j.tvjl.2014.09.005. Mauchle, U., Selvarajah, G.T., Mol, J.A., Kirpensteijn, J., Verheije, M.H., 2015. Identification of anti-proliferative kinase inhibitors as potential therapeutic agents to treat canine osteosarcoma. The Veterinary Journal doi.org/10.1016/ j.tvjl.2014.08.006. Thamm, D.H., Vail, D.M., 2015. Veterinary oncology clinical trials: Design and implementation. The Veterinary Journal doi.org/10.1016/j.tvjl.2014.12.013. Tsai, C.J., Nussinov, R., 2013. The molecular basis of targeting protein kinases in cancer therapeutics. Seminars in Cancer Biology 23, 235–242. Vogelstein, B., Papadopoulos, N., Velculescu, V.E., Zhou, S., Diaz, L.A., Jr., Kinzler, K.W., 2013. Cancer genome landscapes. Science 339, 1546–1558. Webster, J.D., Yuzbasiyan-Gurkan, V., Kaneene, J.B., Miller, R., Resau, J.H., Kiupel, M., 2006. The role of c-KIT in tumorigenesis: Evaluation in canine cutaneous mast cell tumors. Neoplasia (New York, N.Y.) 8, 104–111. Weinstein, I.B., Joe, A., 2008. Oncogene addiction. Cancer Research 68, 3077–3080. Zhang, J., Yang, P.L., Gray, N.S., 2009. Targeting cancer with small molecule kinase inhibitors. Nature Reviews. Cancer 9, 28–39.
Contents lists available at ScienceDirect
The Veterinary Journal j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t v j l
Guest Editorial
Small molecule kinase inhibitors in veterinary oncology
Cancer is a heterogeneous collection of diseases characterized by the following hallmarks: uncontrolled proliferation, resistance to cell death, replicative immortality, resistance to growth suppressive signaling, angiogenesis, and invasion and metastases (Hanahan and Weinberg, 2011). Cancer is due to a combination of mutations, chromosomal rearrangements or aberrations, and epigenetic changes that affect genes, and therefore proteins, that regulate these hallmark phenotypes (Hanahan and Weinberg, 2011; Tsai and Nussinov, 2013; Vogelstein et al., 2013). Recent genomic advances have allowed for the characterization of entire cancer genomes. These efforts have identified an average of 33–66 somatic mutations in common human tumors including breast, colon, and pancreatic cancer (Vogelstein et al., 2013). The goal of targeted therapy is to treat patients through modulation of specific molecular events associated with a patient’s cancer. Targeted therapy may be based on known driver gene mutations, but may also work through modulation of the tumor microenvironment or the immune system. At first glance, targeted therapy appears to be a daunting and potentially unsurmountable task in the presence of 33–66 somatic mutations in a single tumor. However, deeper evaluations of cancer genomes have revealed that there are far fewer driver mutations that are truly responsible for the progression of a given cancer with the remaining mutations merely being passengers. Additionally, these driver genes are members of at least one of 12 signaling pathways (Vogelstein et al., 2013). In the current Special Issue of The Veterinary Journal, Professor Robert Klopfleisch of the Freie Universität Berlin delves deeper into the concept of personalized medicine and the impact that -omic technologies, including genomics, proteomics, and transcriptomics, have played in understanding of cancer biology (Klopfleisch, 2015). Although veterinary medicine is lagging behind advances in human medicine, Klopfleisch provides numerous examples of how his laboratory and others have begun to use transcriptional profiling, proteomic profiling, and other emerging technologies to understand veterinary cancers, to identify prognostic markers or gene expression profiles, and to advance disease detection and evaluations of disease progression (Klopfleisch, 2015). Further optimism for targeted therapies is provided in the concept of oncogene addiction, which is a cancer’s dependency on one or a few genes for continued progression and survival (Weinstein and Joe, 2008; Tsai and Nussinov, 2013). In human medicine, evidence for oncogene addiction has been seen in clinical responses to small molecule inhibitors that target specific mutated or fusion proteins including inhibition of the BCR–ABL protein in chronic myelogenous leukemia, mutant EGFR or ALK fusions in lung cancer, and mutant BRAF in melanoma. A notable theme of the above examples http://dx.doi.org/10.1016/j.tvjl.2015.01.026 1090-0233/© 2015 Elsevier Ltd. All rights reserved.
of small molecule inhibitors is that they all target kinases. With 518 family members, kinases and their phospho-transfer reactions are critical to most signaling pathways and therefore most basic functions of the cell. Targeting kinases’ ATP binding sites allows for somewhat selective kinase inhibition and is relatively well tolerated. Together, the critical role kinases play in cancer progression and the ability to safely and selectively inhibit many kinases has made them a key family of oncology therapeutic targets (Zhang et al., 2009). In the current special issue of The Veterinary Journal, several manuscripts describe recent advances in veterinary oncology to identify, characterize, and target kinases driving canine and feline cancers. With the identification of KIT mutations in approximately 15–30% of canine mast cell tumors (MCTs) (Webster et al., 2006; Letard et al., 2008), the KIT inhibitors toceranib, masitinib, and imatinib have provided the first examples of small molecule kinase inhibitors in veterinary oncology (London, 2014). Toceranib and masitinib have received approval or conditional approval for the treatment of canine MCT from the US Food and Drug Administration (FDA). Mounting evidence from clinical trials suggests that these drugs have increased efficacy in dogs with activating KIT mutations; however, therapeutic benefits have been observed in dogs without these mutations, either through inhibition of related kinases or inhibition of KIT that has increased activation through non-mutational mechanisms (London, 2014). Imitinib is a tyrosine kinase inhibitor that was originally developed to target the BCR–ABL fusion protein in chronic myelogenous leukemia, but also inhibits the receptor tyrosine kinases KIT and platelet-derived growth factor (Capdeville et al., 2002). In this issue of The Veterinary Journal, Dr. Makoto Bonkobara from the Nippon Veterinary and Life Science University describes the use of imatinib to treat both canine and feline MCTs, but also addresses additional studies that have evaluated imatinib in other canine and feline neoplastic and non-neoplastic diseases (Bonkobara, 2015). The use of imatinib in canine and feline MCTs is based on the known role KIT mutations play in MCT progression (Bonkobara, 2015). Similarly, based on previous evidence of decreased Wnt signaling in canine melanoma (Chon et al., 2013) and evidence of an association between Wnt signaling and decreased proliferation in human melanoma (Chien et al., 2009), Chon et al. (2014) evaluated 6-bromoindirubin-3’oxime (BIO), a glycogen synthase kinase-3 beta inhibitor, in canine melanoma cell lines (Chon et al., 2014). This work is a great example of the integration of human and veterinary oncology knowledge to test a therapeutic hypothesis and to develop novel therapeutic strategies. Identification of shared molecular phenotypes of human and veterinary diseases may best enable the identification of targeted therapies that can benefit both species.
Guest Editorial/The Veterinary Journal 205 (2015) 122–123
In contrast to the a priori, hypothesis-driven approaches described above, another manuscript from the current issue of The Veterinary Journal used a kinase inhibitor library screen to identify potential osteosarcoma inhibitors (Mauchle et al., 2015). This screen identified four small molecule inhibitors that inhibit protein kinase C, the IκB kinase complex, epidermal growth factor receptor, adenosine kinase, and multiple serine/threonine kinases. As such, this study identified multiple potential therapeutic targets to explore for treating canine osteosarcoma. However, this study also demonstrated variability in the cell lines’ responses to the inhibitors (Mauchle et al., 2015), highlighting the importance to understand the biology of a given cancer prior to treatment and the importance of biomarkers to identify the activation of the targeted pathway in the cancer. We are only beginning to understand the molecular mechanisms of veterinary cancers and little is known about the molecular drivers of many canine and feline cancers. Identification of molecular targets and biomarkers associated with these targets will be essential to fully harness the power of kinase inhibitors in veterinary oncology. Dr. Lorella Maniscalco and her colleagues at the University of Turin investigated the role of insulin-like growth factor-1 receptor (IGFR-1) in canine osteosarcoma (Maniscalco et al., 2014). In this study, they showed that IGFR-1 is expressed in canine osteosarcoma, provided epidemiological data suggesting that increased IGFR-1 expression is associated with decreased survival, and demonstrated that IGFR-1 inhibition resulted in increased apoptosis in vitro (Maniscalco et al., 2014). The identification and characterization of targets require a combined body of evidence including epidemiological, in vitro, and in vivo data with the final test of the therapeutic hypothesis in well-designed and powered clinical trials (Heller, 2015; Thamm and Vail, 2015). It is anticipated that small molecule kinase inhibitors will play an increasingly important role in veterinary oncology. However, the foundation of this transition rests on the further understanding of the molecular biology of veterinary cancers (Klopfleisch, 2015), the identification of therapeutic targets with relevant biomarkers, and the utilization of rigorous clinical trials to validate therapeutic hypotheses as has been pointed out by two of the review articles in the current issue of The Veterinary Journal (Heller, 2015; Thamm and Vail, 2015). The articles in this Special Issue of The Veterinary Journal on Veterinary Oncology highlight the strides being made to push forward the field of veterinary oncology and provide an optimistic perspective of the future. Joshua D. Webster Department of Pathology, Genentech, Inc., South San Francisco, CA 90480, USA E-mail address: [email protected]
123
References Bonkobara, M., 2015. Dysregulation of tyrosine kinases and use of imatinib in small animal practice. The Veterinary Journal doi.org/10.1016/j.tvjl.2014.12.015. Capdeville, R., Buchdunger, E., Zimmermann, J., Matter, A., 2002. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Reviews Drug Discovery 1, 493–502. Chien, A.J., Moore, E.C., Lonsdorf, A.S., Kulikauskas, R.M., Rothberg, B.G., Berger, A.J., Major, M.B., Hwang, S.T., Rimm, D.L., Moon, R.T., 2009. Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proceedings of the National Academy of Sciences of the United States of America 106, 1193–1198. Chon, E., Thompson, V., Schmid, S., Stein, T.J., 2013. Activation of the canonical Wnt/beta-catenin signalling pathway is rare in canine malignant melanoma tissue and cell lines. Journal of Comparative Pathology 148, 178–187. Chon, E., Flanagan, B., de Sa Rodrigues, L.C., Piskun, C., Stein, T.J., 2014. 6-Bromoindirubin 3’oxime (BIO) decreases proliferation and migration of canine melanoma cell lines. The Veterinary Journal doi.org/10.1016/j.tvjl.2014.07.012. Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: The next generation. Cell 144, 646–674. Heller, J., 2015. Epidemiological and statistical considerations for interpreting and communicating oncological clinical trials. The Veterinary Journal in press. Klopfleisch, R., 2015. Personalized medicine in veterinary oncology: One to cure just one. The Veterinary Journal doi.org/10.1016/j.tvjl.2015.01.004. Letard, S., Yang, Y., Hanssens, K., Palmerini, F., Leventhal, P.S., Guery, S., Moussy, A., Kinet, J.P., Hermine, O., Dubreuil, P., 2008. Gain-of-function mutations in the extracellular domain of KIT are common in canine mast cell tumors. Molecular Cancer Research 6, 1137–1145. London, C.A., 2014. Small molecule inhibitors in veterinary oncology practice. Veterinary Clinics of North America Small Animal Practice 44, 893–908. Maniscalco, L., Iussich, S., Morello, E., Martano, M., Gattino, F., Miretti, S., Biolatti, B., Accornero, P., Martignani, E., Sanchez-Cespedes, R., et al., 2014. Increased expression of insulin-like growth factor-1 receptor is correlated with worse survival in canine appendicular osteosarcoma. The Veterinary Journal doi.org/ 10.1016/j.tvjl.2014.09.005. Mauchle, U., Selvarajah, G.T., Mol, J.A., Kirpensteijn, J., Verheije, M.H., 2015. Identification of anti-proliferative kinase inhibitors as potential therapeutic agents to treat canine osteosarcoma. The Veterinary Journal doi.org/10.1016/ j.tvjl.2014.08.006. Thamm, D.H., Vail, D.M., 2015. Veterinary oncology clinical trials: Design and implementation. The Veterinary Journal doi.org/10.1016/j.tvjl.2014.12.013. Tsai, C.J., Nussinov, R., 2013. The molecular basis of targeting protein kinases in cancer therapeutics. Seminars in Cancer Biology 23, 235–242. Vogelstein, B., Papadopoulos, N., Velculescu, V.E., Zhou, S., Diaz, L.A., Jr., Kinzler, K.W., 2013. Cancer genome landscapes. Science 339, 1546–1558. Webster, J.D., Yuzbasiyan-Gurkan, V., Kaneene, J.B., Miller, R., Resau, J.H., Kiupel, M., 2006. The role of c-KIT in tumorigenesis: Evaluation in canine cutaneous mast cell tumors. Neoplasia (New York, N.Y.) 8, 104–111. Weinstein, I.B., Joe, A., 2008. Oncogene addiction. Cancer Research 68, 3077–3080. Zhang, J., Yang, P.L., Gray, N.S., 2009. Targeting cancer with small molecule kinase inhibitors. Nature Reviews. Cancer 9, 28–39.
