Kevin A. Hahn,     Topeka, Kansas

Targeted Therapies

TKI targeted therapies selectively inhibit protein tyrosine kinases, enzymes involved in cellular signaling pathways that regulate key cell functions and survival. Activation of these enzymes through mechanisms such as point mutations or overexpression can lead to various forms of cancer and nononcologic disorders. Masitinib has been designed specifically to optimize its selectivity against key tyrosine kinases that are implicated in various cancers (primarily KIT [stem cell factor receptor], platelet-derived growth factor receptor, and Lyn [an intracellular kinase of the Src family]) while not inhibiting, at therapeutic doses, those tyrosine kinases or tyrosine kinase receptors associated with possible toxicity (Dubreuil et al, 2009). This degree of specificity contrasts with the TKIs imatinib and toceranib, which inhibit a broader range of kinases as part of a more multitargeted strategy; for example, toceranib inhibits in excess of 50 kinases.

Indications in Veterinary Medicine

To date, masitinib has been evaluated in two pivotal phase III randomized controlled veterinary trials: the first in dogs with MCT (Hahn et al, 2008, 2010) and the second in dogs with atopic dermatitis (Cadot et al, 2011). Observations from these two studies showed that masitinib was effective in managing the disease condition and was generally well tolerated with medically manageable adverse effects. The most common adverse effects that may occur with masitinib are diarrhea and vomiting. To minimize the risk of adverse drug effects, and in particular protein-loss syndrome, regular evaluations that include a complete blood count, serum biochemical evaluation, and urine protein assessment are required.

Additional case studies of on- and off-label use in Europe, along with ongoing in vitro preclinical research, are driving development of further clinical application of masitinib in the treatment of other cancers and as a chemosensitizer for standard chemotherapies (Ogilvie et al, 2011; Thamm et al, 2012). Table 80-1 lists the various oncologic and immune-mediated diseases for which masitinib treatment is being evaluated, along with the associated kinase or cellular target and mechanism of action. Additionally, masitinib is being developed for the treatment of feline disorders, including asthma, injection site sarcoma, and melanoma (Ogilvie et al, 2011). It is interesting to note from a comparative standpoint that masitinib is being investigated for various indications simultaneously in veterinary and human medicine.