Canine mast cell tumors: How do TK inhibitors fit? (Proceedings)

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Canine mast cell tumors: How do TK inhibitors fit? (Proceedings)

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Apr 01, 2010

Introduction to signal transduction

One of the most common questions an oncologist hears from a pet owner is, "Why did my dog get cancer?" While it is often impossible to provide a specific answer for a specific patient, our understanding of why cancer develops has grown exponentially in the past decade. As are most things in the living organism, the causes are extremely complex, multifactorial, and still not completely understood. One basis for understanding how a malignant cell develops comes from knowledge of the normal cellular processes involved in cell division, growth, and differentiation. A critical process in the life of a cell is signal transduction, or transmission of a signal from the outside of the cell to the inside. Cells need to respond to their environment, and signal transduction is a major way in which the cell modulates what it does based on outside factors. Certain proteins found on the cell surface can bind factors and then send a signal into the cell once bound. One such type of signal is sent biochemically via phosphorylation of proteins in a cascade and can lead to cell proliferation, differentiation, and survival via their ultimate effect on gene transcription. If this signaling becomes uncontrolled, cell growth can become unregulated and lead to tumor development.

Tyrosine kinases

Tyrosine kinases (TKs) are a very important class of signaling proteins. They are found not only on the cell surface (these are known as receptor tyrosine kinases [RTKs]), but also in the cytoplasm and the nucleus. In the normal cell, a growth factor can bind to its TK receptor, which then becomes activated and passes on the signal internally via binding adenosine triphosphate (ATP) and then adding phosphate groups to itself (autophosphorylation) and to other molecules farther down the pathway ("downstream"). At least 20 types of protein can be found on the cell surface that are included in the family of RTKs. Examples include Kit, epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR). While TK signaling is critical for normal development and life processes, unregulated signaling can lead to uncontrolled cell growth and survival and thus is one of the underlying causes of some types of cancer. The classic example of TK dysregulation in human cancer is chronic myelogenous leukemia (CML). These cancer cells have a mutation that causes chronic activation of a cytoplasmic kinase (Abl), which leads to chronic abnormal cell growth and survival of these abnormal cells. In dogs, mutations in the RTK Kit, which lead to constant activation, have been found in 20% to 30% of mast cell tumors (MCTs). Dogs with MCTs with Kit mutations have an increased chance of tumor recurrence and a decreased survival time. Mutations in Kit have also been found in gastrointestinal stromal tumors (GISTs–previously called leiomyosarcomas on histopathology). Inhibitors of these kinases, or tyrosine kinase inhibitors (TKIs), are a way to more directly target a cancer cell. TKIs have been approved for treatment of certain types of cancer in humans and, recently, dogs.

Tyrosine kinase inhibitors

The most effective approach to blocking the signaling from RTKs has been to use small molecules that block the ATP binding site of the kinase. With this blockage, TKIs prevent the kinase from phosphorylating and beginning the signaling cascade, which can lead to an inhibitory/fatal effect on the cancer cell itself, or on the blood vessels that are feeding the cancer cells. These TKIs are generally orally bioavailable.

Imatinib mesylate (Gleevec–Novartis) is one of the most successful TKIs in use. It was developed to target the Abl kinase in humans with CML and has dramatically changed the survival rate of that disease: 90% of patients have progression-free survival of at least 5 years. Gleevec binds the KIT kinase as well and has also shown excellent efficacy against human GISTs. Sunitinib (Sutent–Pfizer) was developed to block new blood vessel growth (angiogenesis) and binds RTKs in the split kinase family, including VEGFR, PDGFR, and Kit. Sutent has activity against a number of tumors, including those affecting the colon and breast.