Gerry Polton, MA, VetMB, MSc(Clinical Oncology), DECVIM-CA(Oncology), MRCVS, European Veterinary Specialist in Oncology, RCVS Recognised Specialist in Veterinary Oncology (Small Animals)
Tyrosine kinase enzymes are integral to many processes involved in intracellular signaling. They transduce messages from outside the cell to the cell's nucleus. Many tyrosine kinase interactions are known to influence the growth signaling pathways of the cell; the potential result of aberrant tyrosine kinase signaling is the uncontrolled proliferation of the affected cells. In effect, this is cancer.
With an understanding of the molecular biology of disease we can attribute certain medical phenotypes to specific molecular changes. Molecular changes can result in the altered chemistry of that particular molecule. Since all molecules have a three-dimensional shape, it is possible to use computer software to develop a range of potential drug molecules designed to specifically interact only with the altered target molecule. This interaction can effectively negate the effect of the abnormality, potentially restoring the 'wild type' phenotype.
In order to use TKIs successfully, we need to know our molecular target. The condition for which the first TKI was developed was human chronic myelogenous leukaemia (CML).1 The target for the new drug molecule was the active site of the fusion protein, bcr-abl. This protein is a constitutively active growth-signaling molecule that arises due to a chromosomal translocation event occurring during neutrophil development. The shape of the active site of the bcr-abl fusion protein is similar to that of other tyrosine kinase molecules, so it did not take too long to learn that there were other molecular interactions which could have significant consequences. One such molecular interaction was noted between imatinib and a normal tyrosine kinase molecule, c-kit. Normal c-kit is involved in the transduction of signals involved in gastrointestinal motility and in the coordination of inflammatory responses, among many other functions. Interference with normal c-kit function could be seen as the cause of adverse events associated with the use of imatinib. Medical science being what it is though, it was quickly realised that c-kit was also aberrantly expressed in a different tumour altogether, gastrointestinal stromal tumour (GIST).2 Like CML, GIST is defined by the presence of expression of a specific molecule, in this case c-kit on the cell surface. By targeting the normal c-kit molecule, successful management of GISTs has been achieved.
The discovery that imatinib can be used in the treatment of GISTs illustrates a point at the heart of this presentation, namely that the specificity of TKIs is imperfect; therefore beneficial interactions can be found which allow the successful management of other histologically unrelated tumours. However, the role of imatinib in GIST management was not found by mere coincidence; it did require an intelligent process of scientific discovery to understand the off-target interactions between imatinib and c-kit and the knowledge that c-kit signaling was integral to the survival of GIST cells.
Knowledge of the molecular pathway instrumental to the growth of a specific tumour creates an opportunity to generate a drug molecule that targets this specific process. The first veterinary TKI to be awarded a license was masitinib (Masivet®, AB Science), initially licensed for the treatment of grade 2 or 3 cutaneous mast cell tumours exhibiting a mutation of the c-kit growth factor receptor gene.3 The terms of the license reflected the wisdom that interference with the appropriate target was critical to the success of the therapy. For the first time in history, the veterinary profession was being asked to account for molecular biology in therapeutic decision-making. In the short time since masitinib was made available, it has been recognised that efficacy is not limited to cases with known c-kit mutation only;4 we currently speculate that there is some efficacy achieved through interactions with normal c-kit expressed in mast cell tumours lacking c-kit mutation though the drug definitely performs less well in this group of patients than the group exhibiting mutation.
The second licensed veterinary TKI, toceranib (Palladia®, Pfizer) has a very different spectrum of tyrosine kinase inhibition to masitinib.5 When canine cutaneous mast cell tumours are treated with toceranib, a greater proportion of cases not exhibiting c-kit mutation respond to therapy than we see with masitinib. The presumed explanation for this is that toceranib targets other pathways by which means cell death can arise. The positive impact of this reduced target specificity then is clearly a broader spectrum of tumours demonstrating a measurable tumour response. However, the price paid is the broader range of cellular processes targeted, and the increased risk of morbidity or death as an unwanted consequence.
In medical decision-making, we select therapeutic agents based upon a number of considerations. These include the diagnosis itself, the safety of the agent in question, the probability that the agent will have a favourable impact in the context of the diagnosed cause of illness and non-medical issues like the cost of therapy, ease of administration, and the requirement for and extent of travel and monitoring. Undoubtedly, the medical elements of the decision-making process take primacy. Therefore, in order to make rational prescribing decisions, we need to understand the diagnosis, the medicine, and the interactions that define the positive and negative impacts of medicine administration.
In cancer, we are used to treating tumours largely on the basis of their histological diagnosis. In some tumours we add an extra layer of complexity to the decision-making pathway; for example, in the case of mast cell tumours, we refine our management decisions according to the histological grade of the tumour. It is pertinent to note, however, that histological grade is actually simply a proxy measure. Histological grade has been shown to be something that allows the prediction of tumour behaviour with a degree of reproducibility. Tumour behaviour is a reflection of tumour biology and tumour biology is what we treat with our surgery and medicines.
We have lived and worked in an era of cancer diagnosis by histology and treatment by agents that exhibit reasonably uniform toxic effects. Cytotoxic agents primarily achieve toxicity through interference with the process of mitosis. For this reason the side effect profile of conventional cytotoxic agents is predictable and largely limited to tissues which constantly undergo self-renewal. Tyrosine kinase signaling is integral to almost every function of every living cell. The spectrum of cellular processes potentially affected by the on-target and off-target activity of TKIs is absolute. The interaction profiles for individual TKIs will differ substantially.
Current drug evaluation strategies and regulatory processes do not allow for the identification of all potential interactions between a drug molecule and vital biochemical processes. Ultimately, the true picture of how individual TKIs interact with tumours and patients will only emerge with clinical usage. With the advent of TKIs comes a great opportunity but also a new responsibility. It is incumbent on those of us who choose to use TKIs to ensure that we do so wisely. We must practice good pharmacovigilance and we must work together to best learn how to apply these agents to the greatest good.
1. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. New England Journal of Medicine. 2001;344:1031–1037.
2. Gregory-Bryson E, Bartlett E, Kiupel M, et al. Canine and human gastrointestinal stromal tumors display similar mutations in c-KIT exon 11. BMC Cancer. 2010;10:559.
3. Hahn KA, Ogilvie G, Rusk T, et al. Masitinib is safe and effective for the treatment of canine mast cell tumors. Journal of Veterinary Internal Medicine. 2008;22:1301–1309.
4. Hahn KA, Legendre AM, Shaw NG, et al. Evaluation of 12- and 24-month survival rates after treatment with masitinib in dogs with nonresectable mast cell tumors. American Journal of Veterinary Research. 2010;71:1354–1361.
5. London CA, Malpas PB, Wood-Follis SL, 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. 2009;15:3856–3865.