Kinase inhibitors in cancer therapy

Cancer development requires that tumor cells attain several capabilities, including increased capacity to divide, mobility, anchorage in new place, avoiding cell death (evasion of apoptosis) and growing new blood vessels (angiogenesis) for nutrition requirement and metastasis. Many of these processes involve the actions of protein kinases, which have emerged as key regulators of all aspects of neoplasia or cancer development.

Conventional management strategies in cancer therapy have been relying on surgery, radiation and chemotherapy.

Cancers can be cured if entirely removed by surgery, but this is not always possible. When the cancer has metastasized (spread to other parts of the body) to other sites in the body prior to surgery, complete surgical excision is usually impossible.

Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. It interferes with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.

Some of the cancers like blood cancer (leukemia) and cancer of the lymph nodes (lymphoma) can not be cured by surgery or chemotherapy alone. The treatment of these Leukemia and Lymphomas requires the use of high-dose chemotherapy and radiation treatment known as and Total Body Irradiation. This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. As evident all the above mentioned therapies also target the normal cells as they act against any dividing cell and are not specific for cancer cells.

Many other new therapies are being considered in the treatment of cancer. Since the underlying molecular basis of many cancers lies in the dysfunction of protein kinases, these proteins have become attractive targets for novel anti-cancer drug design called targeted therapy.

Targeted therapy is a type of medication which blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells. Targeted cancer therapies may be more effective than current treatments and less harmful to normal cells.

The first successful kinase inhibitor was used in the treatment of a type of blood cancer, known as chronic myeloid leukemia (CML).

CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome. This chromosomal abnormality is so named because it was first discovered and described in 1960 by two scientists from Philadelphia, Pennsylvania: Peter Nowell of the University of Pennsylvania and David Hungerford of the Fox Chase Cancer Center.

In this translocation, parts of two chromosomes (the 9th and 22nd) switch places. As a result, part of the BCR (expand to "breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa- kilo Daltons). Because abl carries a domain that can add phosphate groups to tyrosine residues, the bcr-abl fusion gene product is also a tyrosine kinase.

The action of the bcr-abl protein is the pathophysiologic cause of chronic myelogenous leukemia. Imatinib (kinase inhibitor) is a new agent, approved by the US FDA in 2001, which specifically targets BCR/abl, the constitutively activated tyrosine kinase fusion protein caused by the Philadelphia chromosome translocation that is felt to be responsible for driving the abnormal cell proliferation of CML. It is better tolerated and more effective than previous therapies.

What are the various kinase inhibitors available for cancer therapy?

Imatinib mesylate (Gleevec®, also known as STI–571) is approved for chronic myelogenous leukemia, gastrointestinal stromal tumor and some other types of cancer. Early clinical trials indicate that imatinib may be effective in treatment of another tumor called dermatofibrosarcoma protuberans.
Gefitinib (Iressa®, also known as ZD1839), targets the epidermal growth factor receptor (EGFR) tyrosine kinase and is approved in the U.S. for non small cell lung cancer. EGFR is also overexpressed in the cells of other solid tumors, such as lung and breast cancers. This leads to inappropriate activation of the apoptotic Ras signal transduction cascade, eventually leading to uncontrolled cell proliferation.Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited; and malignant cells are inhibited.
Erlotinib (marketed as Tarceva). Erlotinib works through a similar mechanism as gefitinib. Erlotinib has been shown to increase survival in metastatic non small cell lung cancer when used as second line therapy. Because of this finding, erlotinib has replaced gefitinib in this setting.
Bortezomib (Velcade®) is an apoptosis-inducing drug that causes cancer cells to undergo cell death by interfering with proteins. It is approved in the United States to treat multiple myeloma that has not responded to other treatments.

New knowledge about the molecular biology of cancer and new tools to specifically target aberrant proteins are opening up new possibilities. Scientists expect in the next two decades to see two competing strategies of cancer therapy: small molecular inhibitors and adoptive immunotherapy.

Dasatinib is a kinase inhibitor of interest for mesothelioma treatment.

Vandetanib (Zactima) for mesothelioma treatment.

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