Kinase Inhibitors in treatment of mesothelioma

Kinase inhibitors are a class of enzymes that regulate cellular and protein pathways by blocking the activity of protein kinases. Protein kinases are enzymes that add phosphate groups to proteins and by doing so cause important chemical, structural, and functional changes to occur. The changes that usually occur alter enzyme activity, the specific function of a target protein, the location of proteins, and protein communication. Each of these processes regulates cellular pathways, cell growth and cell division.

Protein kinases control most processes within cells including conducting signals from one cell to another. This process is known as signal transduction. In addition, protein kinases modify at least 30% of all the proteins in the body. To date, approximately 500 protein kinase genes have been identified, meaning that there could be more than 500 different protein kinase enzymes in the body.

Protein kinases remove one phosphate group from each Adenosine Triphosphate (ATP) it interacts with, which is an energy molecule with 3 phosphate groups. It then adds the phosphate group to other proteins in order to regulate cell activity. Since protein kinases play a significant role in the cell growth, division, communication, etc., over the past years the regulation of kinases became a popular research topic. The inhibition of such kinases may lead to the death or obstructed division of cancer cells. Because protein kinases are activated and deactivated by the addition or removal of a phosphate, they can be inhibited by proteins that bind to the region where the phosphate normally would, thereby blocking the normal activity of the protein kinase.

Abnormal kinase activity is typically the cause of many diseases such as cancer (uncontrolled growth and division of abnormal cells) because in most cases the kinase no longer has the ability to properly control cellular activity. If the activity of an abnormal kinase within a cancer cell is disrupted, the cancer cell may stop growing and dividing. This type of treatment could even lead to cancer cell death, also called apoptosis. In cancer cells, cell proliferation consisting of growth and division along with other cellular pathways are constantly activated because the protein kinases that would normally control such unrestrained growth and division no longer work.

Cancer cells have the ability to grow in the absence of growth factors. Growth factors are chemicals typically secreted by specific cells to bind to the surface of the target cells and stimulate growth. Growth factors are essential for the growth and reproduction of normal, healthy cells and there are several types of growth factors, so that each cell type is affected by different ones. Cancer cells, unlike healthy cells, are able to turn on the cell growth and reproduction process in the absence of growth factors.

This sometimes occurs because the cancer cells contain mutated kinase genes. For example, in chronic myeloid leukemia (cancer of the bone marrow) a mutation called a chromosome translocation causes a certain kinase within the cancer cells to be constantly active. In other words, the affected protein kinase is always "on." Because this kinase is constantly on, the cancer cells grow out of control. This understanding led to idea of inhibiting the specific activity of kinases known to play a role in different forms of cancer and led to the production of kinase inhibitors to prevent cancer cell proliferation. Currently four kinase inhibitors are commonly used to treat cancer: Sorafenib (Nexavar), Imatinib (Gleevec), Gefinitib (Iressa), and Lapatinib (Tykerb). There are many others, but these four are some of the more widely used ones.

Sorafenib is a newer form of kinase inhibitor that blocks the activity of several kinases that play a role in cell division. More specifically, Sorafenib disrupts the activity of various targets such as growth factor receptors and tyrosine kinase receptors. These types of receptors receive signals that stimulate cancer cell growth directly or indirectly. Using Sorafenib to block the activity of these receptors can reduce cancer cell division and lead to cancer cell death. This inhibitor may also be able to disrupt a process called angiogenesis, which is the formation of new blood vessels that provides the nutrients cancer cells need in order to grow and divide. Angiogenesis is the critical factor that determines whether or not cancer cells will develop into growing, malignant tumors. The use of this drug was approved in 2005 to treat renal (kidney) cell cancer and in 2007 to treat inoperable liver cancer. The ability of Sorafenib to treat other forms of cancer is still under investigation.

Imatinib is a tyrosine kinase inhibitor that prevents the release of signals from enzymes within cancer cells that would lead to the growth, division, and the spread of cancer throughout the body. Tyrosine kinase is an enzyme that plays a role in cellular pathways and cell communication. This enzyme has an Adenosine Triphosphate (ATP) binding site and when ATP (the energy molecule) binds to this site the enzyme becomes activated and stimulates cell division. Imatinib binds to the binding site of tyrosine kinase, preventing the binding of ATP, and thereby hindering the growth and division of cancer cells.

Imatinib was first used for the treatment of chronic myeloid leukemia (CML), which is the occurrence of too many underdeveloped white blood cells in the bone marrow. CML develops when a chromosome mutation causes two separate genes located in white blood cells to fuse and become an oncogene (a gene responsible for cancer development). This oncogene produces an abnormal tyrosine kinase receptor that stimulates cell growth and reproduction in the absence of essential growth factors. This leads to the uncontrollable growth of underdeveloped white blood cells. The use of Imatinib was approved in 2001 to treat CML, in 2002 to treat gastrointestinal stromal tumors (GIST), and in 2006 to treat pediatric CML. In 2006 Imatinib was also approved to treat chronic eosinophilic leukemia (a type of cancer characterized by a high amount of white blood cells in the bone marrow), dermatofibrosarcoma protuberans (skin cancer), aggressive systemic mastocytosis (blood cancer), and myelodysplastic or myeloproliferative conditions (blood and bone marrow diseases).

Gefinitib is another type of tyrosine kinase inhibitor cancer medication that inhibits the normal function of the epidermal growth factor receptor (EGF receptor). The EGF receptor has a binding site for EGF, which is a small protein that is important for cell growth and differentiation. Differentiation is the maturation of cells that allows them to fulfill their functional role in the body. A large number of EGF receptors can usually be found in various types of cancers. This over-expression or higher than normal amounts of EGF receptors appears to cause various forms of cancers to develop and spread or metastasize throughout the body very quickly. Gefinitib binds to the EGF receptor, blocks the tyrosine kinase, and switches off the signal that causes cancer cells to grow uncontrollably. This inhibitor was approved in 2003 as a third-line form of treatment for non-small cell lung cancer that was not responsive to first- and second-line treatments such as chemotherapy.

Lapatinib functions like a tyrosine kinase inhibitor, but is actually a small molecule that inhibits the epidermal growth factor receptor (EGF receptor) and the human epidermal growth factor receptor 2 (HER2). Both of these receptors are found on the surface of cells and they bind to growth factors that activate signaling cascades that stimulate cell division. Lapatinib competes with ATP to bind a site on the tyrosine kinase domain of proteins that would normally cause a signal, thereby preventing the normal signal. In 2007 lapatinib in combination with capecitabine (a chemotherapeutic drug) was approved to treat metastatic breast cancer. This type of cancer usually has an over abundance of the EGF receptor and HER2. In addition, since Lapatinib is a small molecule that can pass the blood-brain barrier (the protective barrier around the brain), its effectiveness in treating brain metastasis is currently being investigated.

A few cautions need to be considered before this inhibitor is taken. This drug has been shown to lower left ventricle ejection fraction (LVEF) in certain individuals, meaning that it can lower the efficiency of the heart. Lapatinib may also be toxic for the liver in individuals who already have liver problems. Individuals considering taking Lapatinib should undergo a thorough doctor's examination before taking this drug. In addition, women who are pregnant, may become pregnant or are breast feeding should avoid taking Lapatinib because this drug may affect a fetus or baby. Studies regarding the exact effects that lapatinib have on the liver and on fetuses are currently ongoing. To date, it has been shown that Lapatinib is absorbed into the breast milk of mothers and can therefore be ingested by babies, though the harm this may have on a growing fetus or baby is unclear.

A large number of additional kinase inhibitors are currently being analyzed, tested, and clinically used to treat various forms of cancer. As researchers learn more about specific kinases and the roles they play in certain cancers, more effective types of kinase inhibitor cancer drugs will be developed. It is the hope of the pharmaceutical companies developing these drugs that the kinase inhibitors they produce will ensure that cancer cells, and only cancer cells, are targeted during treatment. Because protein kinases play an essential role in such a large number of cellular pathways in the body it is important not to disrupt any of the normal duties of the kinases by the administration of kinase inhibitors. It is also important that a doctor fully understands a patient's physical condition and the medicines they are taking that may interfere with a kinase inhibitor that is prescribed as a method of cancer treatment.

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