Making the Connections for a Targeted Cancer Treatment Takes Time and Perseverance
May 10, 2001, marked an important milestone in the fight against cancer. News outlets all over the country announced that a promising drug called Gleevec™ had been approved to treat a serious blood cancer known as chronic myelogenous leukemia (CML). The drug is one of the first of its kind to be approved - a targeted agent that hones in on specific molecules in cancer cells, leaving healthy cells unharmed.
But the development of Gleevec™ is far from an overnight breakthrough. The road to its discovery was paved through knowledge culled from more than 40 years of studies probing the molecular events associated with cancer development, the use of new technologies that enabled scientists to move in directions previously beyond reach, and quite often, unanticipated opportunity.
The story involves four key steps: learning the unique chromosomal abnormalities of CML, identifying the related cancer-causing protein, finding a treatment that targets that protein, and testing and proving its effectiveness and readiness for use in treating cancer.
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The Philadelphia Chromosome: Uncovering the Fundamental Nature of CML
1960 The story really began in 1960 when Drs. Peter Nowell and David Hungerford - two Philadelphia-based physicians - made a curious discovery. While testing a new laboratory technique, they noticed that cells from CML patients were missing a short segment on one member of the 22nd pair of chromosomes. This shortened chromosome became known as the "Philadelphia chromosome."
It was the first chromosome abnormality ever found to be associated with a specific cancer and the first indication that tumors might indeed arise from changes beginning in just one cell. While the link between the Philadelphia chromosome and CML led scientists to suspect a causal relationship, the location of the missing DNA from chromosome 22 and how it might lead to CML was a mystery to be solved over the next three decades.
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1970 In the early 1970's, new staining techniques offered a way to more precisely visualize band patterns - characteristic markings that can be used to identify individual chromosomes. With this technique, Dr. Janet Rowley determined that chromosome 9 in CML patients was lengthened by the same amount that chromosome 22 was shortened. From this observation, Rowley proposed that the genetic material from the two chromosomes was reciprocally exchanged, or "translocated."
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1980 Using newly developed approaches for molecular analysis, scientists in the early 1980s determined that the genetic rearrangement that leads to the Philadelphia chromosome occurs when genetic mistakes cause breaks in the middle of two vital genes located on chromosomes 9 and 22.
They found that the break on chromosome 22 occurs in the middle of the bcr gene and that the break on chromosome 9 occurs in the abl gene. On the shortened end of chromosome 22, the genetic rearrangement produces the abnormal bcr-abl gene, the source of CML development.
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Characterizing the Cancer-Causing Protein
In 1986, Dr. David Baltimore and his research group led the effort to isolate the bcr-abl gene and characterize its activity. These scientists determined that, like the normal abl gene, the defective bcr-abl gene carries the code for a tyrosine kinase, a class of proteins that plays an important role in regulating cell growth and division. The normal abl gene will turn on or off, producing tyrosine kinase to promote cell growth as needed. The aberrant bcr-abl gene, however, is always turned on because it lacks a critical piece that enables the gene to turn itself off.
As a consequence, bcr-abl floods the cell with the instruction to divide constantly and also prevents the leukemia cells from undergoing normal programmed cell death or apoptosis, a process that helps to regulate white blood cell numbers. When several laboratories determined that the the bcr-abl gene was all that was needed to induce leukemia in mice, the link between the hybrid gene and CML was confirmed.
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Developing a Targeted Treatment
During this same time period, advances in molecular biology were revolutionizing the field of drug discovery. In the laboratories of Ciba-Geigy (a Swiss pharmaceutical company that later merged with Sandoz to form Novartis, the company that ultimately produced Gleevec™) scientists were able to apply unfolding knowledge about the workings of cellular pathways and communications systems in a number of drug development efforts.
In one research program, scientists were looking for agents to inhibit protein kinases - a group of cell signaling proteins that includes the Abl protein. A number of such agents were found, including one that they labeled STI571. This agent would later be renamed Gleevec.
1990 The development of STI571 would proved to be momentous to an American oncologist named Brian Druker. Dr. Druker was interested in determining how the Bcr-Abl protein, the product of the bcr-abl gene, fits into the complicated circuitry of cell signaling. His research led him to believe that the Bcr-Abl protein could be a powerful target for a drug that could impede the activity of the protein and be an effective treatment for CML.
When he learned about Ciba-Geigy's complementary research, Druker asked scientists there for candidate protein kinase inhibitors that he could test against leukemia cells grown in his laboratory. At the end of 1993, the pharmaceutical company sent him several candidates, including STI571. Druker screened the chemicals and found that STI571 halted the growth of the leukemia cells but had little effect on healthy ones.
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Testing and proving STI571's effectiveness
While this was an exciting outcome, there were still many obstacles to overcome. The process of developing a new drug and getting it approved for use is lengthy and expensive. Scientists must: identify a possible agent , study and test its efficacy, perform pharmacology, and toxicology studies of the agent, file with the Food and Drug Administration, and finally evaluate it through clinical trials
STI571 posed an additional business problem because the incidence of CML is quite low, limiting the potential demand for the drug.
Further, two moderately effective treatments already were available for CML, although both held potential for serious side effects. Interferon therapy could produce partial or complete remission in patients in the chronic stage of the disease but often with serious side effects. Bone marrow transplant more reliably produced a cure, but many CML patients are not young or healthy enough to tolerate a transplant.
Despite reservations, Novartis agreed to produce enough STI571 for an initial clinical trial. Dr. Druker began the Phase I trial, conducted to identify a safe dose level, in June of 1998. By December of 1999, he and his colleagues reported that white blood cell counts for all of the 31 patients receiving a high dose of STI571 had returned to normal, an effect that was sustained for the eight months that the patients stayed on the drug.
In 9 of the 20 patients who were treated for five months or longer, no leukemia cells could be found, confirming that the drug was eliminating the source of the cancer and with minimal side effects. Rarely are such dramatic results seen in a Phase I trial.
2000 In response to these exciting findings, Druker and his colleagues conducted a larger study and reported in April 2001 that STI571 restored normal blood counts in 53 of 54 CML patients, all of whom had been resistant to previous chemotherapy. Of these patients, 51 were still doing well after a year on the medicine, with most reporting few side effects.
Following "fast-track" review, the Food and Drug Administration approved STI571, now known as Gleevec™, as a treatment for CML in May 2001, beginning with patients not responding to standard therapies.
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The Story Continues
But the story of Gleevec™ as a treatment for CML is not complete. Patients receiving the drug need to be followed for longer periods to determine whether positive effects will last and long-term treatment can cause side effects
Unfortunately, most patients with advanced disease relapse within a year. The cause of resistance is now known, so scientists are trying to overcome it. Like most successful treatments, Gleevec will undoubtedly spawn a host of refinements.
The story does not end with CML. In addition to the Bcr-Abl signaling protein, the drug appears to target two other protein kinases, the c-kit receptor and the PDGF receptor. The c-kit receptor is active in gastrointestinal stromal tumor (GIST), a cancer that affects connective tissue in the digestive system and the PDGF receptor associated with many types of cancer, including a form of brain cancer called glioblastoma.
NCI-supported and private-sector scientists are investigating the effectiveness of Gleevec™ against cancers of the breast, ovary, and lung.
The success of Gleevec™ offers substantial hope that molecular targeting is a highly effective strategy in the fight against cancer, provided that the target is carefully chosen and validated. As scientists identify additional cellular mechanisms that drive tumor growth, it will be possible to design tailor-made agents that selectively take aim at these targets to thwart the growth of specific cancers.
It is likely that Gleevec™ is the first of many potent, but safer, targeted preventive and treatment drugs to be developed as a result of advances in our understanding of cancer at the molecular level.
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