CML, Gleevec and Targeted Drugs
Every year, 30,000 people in the United States are diagnosed with chronic myelogenous leukemia, or CML. CML targets the white blood cells known as myeloid cells that are manufactured in the bone marrow and causes them to grow abnormally. Normally, cells will divide and later self-destruct in an orderly manner as regulated by a cell cycle and checkpoint system; however, in cancer, the cell�s genetic blueprints are damaged, causing its cell division mechanisms to be turned on indefinitely and preventing the cell from maturing properly, thus not allowing the cells to die. The rapidly dividing cells fill the bone marrow and spread around the body through the lymphatic and circulatory systems, preventing the manufacture of healthy cells and exposing the body to increased risk of infection and bruising. External symptoms include anemia, fatigue, repeated infections, enlarged spleen and unusual bleeding. Though this disease is usually fatal, treatments have been found that successfully reverss the effects of the cancer by aiming at the mechanisms by which CML perpetuates itself, most notably imanitib mesylate or Gleevec.
Current treatments for CML include transplantation and interferon therapy, which attempt to restart the immune system, and radiation therapy and chemotherapy, which attempts to kill the rapidly dividing cancerous cells with radiation and chemicals respectively. Chemotherapy works by inhibiting DNA synthesis and thus killing all cells that need to rapidly divide, including both cancer cells and normally rapidly dividing cells. The principle behind chemotherapy is that the cancer will have been defeated when all the cancer cells are killed, and so drugs of high toxicity are used to achieve that end. However, these drugs can also cause further cancers, and are used in combination with drugs of low toxicity to contain the damage. Even though these treatments do extend the life of a cancer patient, they are not ultimately very effective; current drug research raises the effectiveness of newly designed drugs by more specifically targeting them to the specific mechanisms by which cancer is caused.
The first step to identifying the oncogenic mechanism was taken in 1961, when a study linked CML with the presence of a chromosomal aberration known as the Philadelphia (Ph) chromosome. The fact that 90% of all CML sufferers today have this chromosome was strong evidence of a genetic link to CML. At first, it was believed that the Ph chromosome was a mere marker of malignancy, but further study showed that the aberrant chromosome did actually have a causative role in cancer.
Initial analysis was not able to pinpoint the exact nature of the aberration; later studies concluded that it was actually a translocation � a joining of segments from different chromosomes. This chromosome, as well as any other chromosome, contains genes coding for proteins that are needed to maintain body functions. Specifically, the genes implicated in the translocation were the c-ABL locus on chromosome 9 that codes for a tyrosine kinase, and the BCR locus, or breakpoint cluster region, on chromosome 22. Tyrosine kinases are a class of enzyme that phosphorylates, or adds phosphate groups to, the amino acid tyrosine. ABL, with one base mutation, can turn into an oncogene, extending signaling indefinitely. The BCR-ABL gene was further implicated in cancer by the discovery that its products included P210, an active protein associated with CML. Other scientists observed that in the rare case of CML patients not having the Philadelphia chromosome, the BCR-ABL fusion gene was still present, though on a normal chromosome 22. In the search for a mechanism to cancer, the first step had been discovered and a possible drug target identified in the BCR-ABL gene.
To further define the specific target area of an anti-cancer drug, scientists delved further into the mechanisms by which BCR-ABL can initiate the process leading to cancer. These studies were able to define a participatory link between the BCR-ABL protein complex and the Ras signaling pathway, a molecular communication conduit for cell division. One study found that BCR-ABL regulates c-RAF-1, a downstream effector of the Ras pathway. Another study found that BCR-ABL was able to upregulate the Ras pathway through an adaptor protein called GRB-2, an anchorage molecule within the cell scaffolding. Upregulation of the Ras pathway effectually increases signal traffic and allows heightened levels of unregulated growth for an indefinite time. These findings were very important in establishing a linkage between the BCR-ABL protein and the direct cause of an important symptom of cancer.
Another finding strengthening the importance of BCR-ABL in the oncogenic mechanism was the discovery of a linkage to Bcl-2, a gene intimately involved with apoptosis. Normally, when cells are damaged, Bcl-2 will signal other proteins to start apoptosis, but heightened levels of Bcl-2 were preventing cell apoptosis in certain cancers, which were also associated with chromosomal translocations. Apoptosis was quickly reached in the absence of a normal growth factor, but within cells containing both BCR-ABL and Bcl-2, cell division continued in defiance of apoptosis. Scientists were then able to conclude that Bcl-2 was an important mediator in the BCR-ABL pathway to cancer.
In the search for a successful treatment, scientists now had a suitable target: BCR-ABL. Not only are its protein products a positive marker of cancer, it is linked to the specific symptoms of cancer � unregulated cell division and inactive apoptotic mechanisms. A vaccine, created by the Memorial Sloan-Kettering Cancer Center, uses the BCR-ABL fusion gene as a target to stimulate patient immunity to their cancer cells and to the proteins that cause the disease. Other such drugs designed around this target work under the assumption that a blockage of BCR-ABL activity will reverse the cancer phenotype; these include CGP 57148 and imanitib mesylate. The blockage of activity is achieved by blocking the ATP binding site of the kinase, thus removing the source of the phosphate groups which ABL uses in its function as a tyrosine kinase.
Imanitib mesylate, otherwise known as STI 571 or Gleevec, is currently the most active and practical agent yet discovered against CML. Though allogeneic stem cell transplantation can potentially cure CML, it is impractical because of the difficulty in matching donors to those in need. Studies have shown that it eradicates CML cell proliferation in mice and inhibits the proliferation of CML cells in the lab, which are derived from cell lines and actual CML patients. Toxicology studies have determined that the drug is safe for human trials; clinical trials returned sufficient success rates in treating Ph+ CML. In 2001, imanitib mesylate was finally approved for use in the US by the FDA under the trade name Gleevec. A February 2002 paper in the New England Journal of Medicine said that 95% of treated CML sufferers are still alive after 18 months, and 60% of patients achieved a major cytogenetic response � less than 1% presence of Ph chromosome in the cells of the bone marrow. A later study in the same journal found Glivec to be 9 times more likely to stimulate a full cytogenetic response than more traditional drug treatments.
For those many Americans who suffer from CML every year, the prognosis can be much improved from use of such effective drugs in combination with other treatments. Imanitib mesylate or Gleevec, the most potent example, was discovered through research into the mechanisms by which cancer spreads � particularly, the BCR-ABL gene as a major focus. Future research could possibly reveal better treatments using increasingly more potent knowledge of the oncogenic mechanism.