A Story of Discovery: Gleevec Transforms Cancer Treatment for Chronic Myelogenous Leukemia
- Prior to 2001, less than 1 in 3 chronic myelogenous leukemia (CML) patients survived 5 years past diagnosis.
- Today, there is new hope thanks to decades of NCI-supported research that contributed to the discovery of imatinib, a targeted treatment for CML.
- Imatinib (Gleevec) is a tyrosine kinase inhibitor (TKI).
- The development of imatinib taught scientists that understanding the specific biology of a disease can lead to better cancer treatments or even a cure.
- The development of TKIs led to breakthrough treatment of CML and a number of other cancers, including some forms of gastrointestinal stromal tumors (GIST) and some forms of acute lymphoblastic leukemia (ALL) in children.
- Building on previous work, NCI-supported researchers continue to study the role of damaged genes in cancer, such as chromosomal translocation.
The revolutionary cancer drug imatinib (Gleevec) is part of a new group of targeted treatments designed to attack a specific cancer-causing molecule. Since its introduction as a treatment for CML in 2001, imatinib has been shown to be effective against a number of other cancers, including some forms of ALL in children.
Pathway to Discovery
Scientific breakthrough is often a fortuitous blend of incremental advances built on the work of others. Imatinib resulted from decades of research anchored by small but significant discoveries in basic research. In 1960, Peter Nowell, M.D., of the University of Pennsylvania, and David Hungerford, Ph.D., of the Fox Chase Cancer Center in Philadelphia, reported finding an abnormally short chromosome in bone marrow cells from patients with CML. The tiny chromosome was quickly dubbed "the Philadelphia chromosome" for the city in which it was discovered, but its origin and role in CML remained a mystery.
In the early 1960s, genetic research was in its infancy. Laboratory tools and techniques for analyzing DNA and identifying individual genes had not yet been invented. Sometimes, according to Dr. Nowell, simply getting an accurate count of chromosomes isolated from tumor material was difficult, let alone being able to tell one chromosome from another.
Not until the 1970s did researchers learn how the Philadelphia chromosome was formed. In 1973, using new DNA-staining technology, Janet Rowley, M.D., of the University of Chicago, discovered that chromosome 22 and chromosome 9 had exchanged bits of DNA. This phenomenon is known as chromosomal translocation—when one piece of a chromosome breaks off and attaches to another or when pieces from two different chromosomes trade places. Translocation would prove to play a key role in other forms of cancer as well.
In the 1980s, Nora Heisterkamp, M.D., then an NCI intramural scientist and now of Children’s Hospital in Los Angeles, and her colleagues figured out that translocation resulted in the fusion of two genes that created a new gene known as BCR-ABL. In 1986, Owen Witte, M.D., and his colleagues at UCLA discovered that this fusion gene causes the body to produce an abnormally active form of an enzyme called a tyrosine kinase that stimulates uncontrolled cell growth in white blood cells.
As a result of these discoveries, researchers had a target for treatment. If this highly active enzyme could be suppressed, CML might be treatable. This idea, however, still had to be tested.
By this time, Brian Druker, M.D., of Oregon Health and Science University, had already been studying tyrosine kinases as possible targets for precisely aimed treatment and he was focusing on CML as a promising disease to study. Although CML is relatively uncommon— striking about 5,000 Americans a year—its cause appeared relatively simple. CML is not the result of a series of gene mutations, but rather is caused by one translocation resulting in a singular mutation: the BCR-ABL fusion gene.
In 1993, Nicholas Lydon, M.D., who led a drug discovery group at the pharmaceutical company Ciba-Geigy (now Novartis), approached Dr. Druker with his vision to develop a drug that turns off enzymes that cause cancer. Because CML has a singular mutation, these researchers targeted this disease and began screening compounds developed by Dr. Lydon’s lab. Eventually, Dr. Druker found one compound, called STI571, that was more effective than others. This compound, which eventually became known as imatinib, would kill every CML cell in a petri dish, every time.
Turning Discovery into Health
Imatinib’s performance in clinical trials was stunning. In the first human trial, which began in 1998, this drug restored normal blood counts in all 31 patients who took at least 300mg a day. In later trials, blood counts returned to normal in about 95 percent of patients who were in the initial phase of CML when the cancer is growing slowly. The results were impressive, if less dramatic, for patients whose CML was more advanced.
Before the introduction of imatinib, a diagnosis of CML amounted to a death sentence. Now, most cases of CML can be controlled, and researchers have developed new medications to counter resistance to the drug when it arises. A 2011 study concluded that CML patients whose disease is in remission after 2 years of imatinib treatment have the same life expectancy as those who never had this disease. Imatinib opened a new era of successful treatment, putting an end to treatments with serious side effects that had limited success in prolonging life beyond the first year of diagnosis. Essentially, imatinib can stop the CML clock from ticking. Dr. Druker says that patients "won’t die of CML."
Research to Practice: NCI's Role
Science advances incrementally and many small steps are often needed to achieve a big discovery. Basic research stimulates scientific discovery to solve critical questions and add to our understanding of biological processes and abnormalities in cancer. NCI’s longstanding commitment provides vital support to sustain diverse cancer research.
The development of TKIs like imatinib led to breakthrough treatment of CML and a number of other cancers. Prior to the discovery of BCR-ABL, researchers had limited understanding of the role of chromosome abnormalities and cancer. Supported by an NCI career development award, Dr. Druker and researchers at the Dana-Farber/Harvard Cancer Center and the Oregon Health and Science University Knight Cancer Institute—both NCI-designated cancer centers—conducted research that contributed to the series of discoveries leading to imatinib. These collaborations, along with NCI-funded genetic research technology and techniques, led to discoveries that shed critical light on new and potential ways to improve cancer treatment.
We are making significant progress in the fight against cancer and are providing hope to millions of patients and their families…. We are well on our way to making effective and nontoxic therapies a reality for all cancer patients.
What's Next for Gene-Fusion Research?
The story of the Philadelphia chromosome doesn’t end with the development of imatinib as a highly effective treatment for CML. Research growing out of the discovery of chromosomal translocations is moving down several different research paths.
Knowledge gained from the imatinib breakthrough has revolutionized treatment and improved outcomes for patients with advanced GIST, and has led to significant increases in survival. More than 80 percent of GIST tumors shrink or disappear after imatinib treatment. The science behind targeted CML treatment has also helped scientists better understand drug resistance and inform the development of newer TKIs like nilotinib, dasatinib, and ponatinib, which offer CML patients more treatment options.
Fusion genes, formed when chromosomal translocations collapse two genes into one, are now implicated in a wide variety of cancers. These include lung, colorectal, pancreatic, prostate, endometrial, and thyroid cancers, as well as several forms of leukemia and lymphoma. Many of these cancers involve genes other than the BCR-ABL combination that causes CML, but overproduction of tyrosine kinases and other molecules that prompt uncontrolled cell division is a common theme. Some of the cancers associated with such damaged genes have responded to imatinib or other TKIs.
Recently, researchers detected even more complicated rearrangements of genes in cancer cells—multiple breakpoints that fuse some genes and disrupt others. Many cases of such widespread DNA damage, called complex genomic rearrangements, may remain to be discovered, but new computer-based technologies—such as advanced DNA sequencing and other specialized processes or calculations that can number breakpoints—will be needed to find them.
Identification of damaged genes that play a role in cancer can be the first important step toward a cure. Understanding how the disease is caused points the way for research aimed at preventing or treating cancer. This process led to the discovery of imatinib and is paving the way for other exciting advances in cancer research.
NCI-supported research led to a series of discoveries that resulted in the development of imatinib (Gleevec), a landmark targeted cancer drug that transformed cancer treatment and continues to save lives.
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