Author: Redig Mandy
Date: September 2005
Despite billions of dollars, decades of research, and an unparalleled level of international cooperation between research scientists and clinicians, cancer remains a major cause of death worldwide. Therapies have improved and many forms of cancer are now treatable, but the disease still kills over six million people throughout the world each year (Globecan 2000). For this reason, cancer research funding through the National Institute of Health (NIH) and the National Cancer Institute (NCI) represents one of the largest expenditures of the United States federal government. This focus on research has led to improved medical treatments for cancer as well as greater understanding of the molecular intricacies of the disease. Cancer is now considered not simply one disease but rather a multitude of independent disorders that can all result in malignant cellular growth. Unlike other diseases, there is no simple explanation, or even definition, for cancer, and so there is no simple way to treat it. The dream of a cure for cancer, the "magic bullet" to miraculously eliminate the disease, is now considered unrealistic in light of overwhelming complexities.
However, an interdisciplinary approach has emerged offering new hope for cancer therapies. Standard chemotherapy or radiation regimens are nonspecific in their targeting of cancer cells. In contrast, this new field of therapy reflects a growing awareness on the part of the oncology community that the most effective way to treat a tumor is to target the specific molecular mechanisms responsible for its uncontrolled growth. Research has shown that not all tumors are the same; molecular targeting, the attempt to tailor therapy to the specific abnormalities causing disease, has become one of the most promising areas in cancer biology research. In addition, as a specific application of molecular targeting, pharmaceutical research has combined the basic science of molecular biology and biochemistry with combinatorial chemistry and organic synthesis to create a new field: rational drug design.
Unfortunately, drug development takes time, and it is years, often decades, before a drug that shows promise in the lab will make it into the clinic. Rational drug design, because it narrows the focus on possible therapeutic agents, is a potential way to shorten this lengthy process. The inherent benefits of the approach are highlighted by one of the most exciting developments in cancer biology in recent years. On May 10, 2001, as a result of overwhelmingly positive clinical trials, the Food and Drug Administration (FDA) approved Novartis Pharmaceutical's Gleevec (imatinib mesylate) for use in the treatment of chronic myelogenous leukemia (CML). In a stunning validation of the value of rational drug design, Gleevec is the first of a wave of compounds with the potential to revolutionize the way we look at cancer.
The Target - Chronic Myelogenous Leukemia
Leukemia is a disease of the white blood cells. While normal white blood cells, or leukocytes, are responsible for maintaining the immune system, the abnormal proliferation of such cells leads to a deadly form of cancer. Chronic myelogenous leukemia (CML) is characterized by the accumulation of immature granulocytes, a specific type of white blood cell. The disease progresses through three stages, and the specific stage of disease in a patient is crucial in planning treatment. In stage one, also known as chronic phase, there are few if any outward symptoms of disease; many CML patients are unexpectedly diagnosed as the result of blood work following a routine doctor's appointment. After a period of up to several years, chronic phase CML progresses to accelerated phase CML, which is characterized by an increasing ratio of malignant to normal white blood cells. The final stage of CML is known as blast crisis, and by this point almost a third of blood and bone marrow cells are cancerous. Due to their high numbers, some of these blast cells may metastasize and form tumors in other tissues including the bones or lymph nodes. Until recently, the most effective form of treatment for CML was the use of a compound called alpha interferon which was often followed by high dose radiation, chemotherapy, and a bone marrow transplant. However, as CML progresses, the efficacy of bone marrow transplants decreases sharply. Transplants done in the accelerated or blast crisis phase have a high rate of failure. Only 15% of patients transplanted in blast crisis are still living after five years (Leukemia Society).
Despite the grim prognosis for CML patients, there is one crucial molecular detail of the disease that renders it a promising target for rational drug design. The highly specific targeting that led to the laboratory development of Gleevec can be traced back to some of the early studies of leukemia. The first piece of the puzzle was uncovered in 1960 when it was discovered that nearly all patients with CML possess an abnormally small chromosome 22. This abnormality was nicknamed the Philadelphia chromosome and has since become known as CML's cytogenetic calling card. Shortly thereafter it was discovered that chromosome 9 was elongated by approximately the same length as the missing region of chromosome 22; these findings were eventually linked after molecular characterization confirmed a translocation between chromosomes 9 and 22. In the process of this exchange, breakpoint cluster region (bcr) proteins from chromosome 22 become fused with the c-abl oncogene from chromosome 9 thus creating a hybrid bcr-abl gene. A normal c-abl gene encodes a protein that is highly regulated; the functional enzyme is shuttled between the nucleus and cytoplasm of a cell so that it is only activated when needed. However, under the influence of bcr resulting from bcr-abl fusion, c-abl loses the checkpoints intended to hold it under control. The enzyme becomes a constitutively-active cytoplasmic protein. Studies in mice have shown that the introduction of the bcr-abl fusion protein, regardless of the presence of the Philadelphia chromosome, is sufficient to experimentally induce the development of CML.
The consequences of the bcr-abl abnormality are devastating because of the resulting c-abl enzyme that is produced. This unregulated enzyme, a tyrosine kinase, is the molecular cause of CML. Kinases are enzymes that transfer phosphate groups from ATP to particular residues, in this case tyrosines, of target proteins within the cell. Phosphorylation often serves as a molecular switch to activate or inactivate a range of proteins involved in such vital activities as cellular growth, development, and survival. For this reason, kinases are normally kept under tight control; a runaway kinase can promote the excessive proliferation associated with cancers including CML.
The Gleevec Application
Since abnormal enzymes are implicated in a variety of human cancers, targeting the mutant function should have deleterious affects for the tumor while leaving normal tissue unaffected. As a result of studies highlighting the molecular mechanisms of CML, a search began for compounds to inhibit the runaway bcr-abl kinase. Compound screening at Novartis Pharmaceuticals in the early 1990's identified 2-phenylaminopyrimidines as a general class of kinase inhibitors, and subsequent chemical synthesis was used to design a series of compounds that should have more specific anti-tumor effects. One of the drugs in this class was called STI571.
In vitro studies using STI571 demonstrated that it was a highly effective and specific inhibitor of platelet-derived-growth-factor (PDGF) kinases, c-kit kinases, and c-abl kinases. STI571 acts by blocking the ATP-binding site of these enzymes. The functional form of the enzyme uses ATP as its source of phosphate groups, thus by blocking the ATP-binding site of the kinase, STI571 prevents the enzyme from becoming active. In the case of bcr-abl kinases, further experiments demonstrated that STI571 inhibited growth in cell lines carrying the bcr-abl mutation. Animal models produced data indicating an STI571 dose-dependent inhibition of tumor growth although tumors were not completely eliminated.
On the basis of promising laboratory data, STI571 began clinical trials in 1998. The first trials were conducted in patients with chronic phase CML who had previously failed interferon therapy. As with any Phase I clinical trial, the main purpose of the study was to determine the overall safety and acceptable dose ranges of the drug. However, in the midst of safety evaluations, the physicians running the trial noticed that with elevated doses of STI571 an astounding 98% of the patients showed a complete hematologic response - the abnormal Philadelphia chromosome was still detectable, but the elevated levels of circulating white blood cells, the cause of CML symptoms, were gone (Mauro and Druker).
Due to these astonishing results, more expansive Phase II trials were conducted in over 1000 patients representing a range of CML stages, 27 cancer centers, and six countries. In the 532 chronic phase patients, the results of the original trial were confirmed. Only 3% of patients experienced disease progression while a mere 2% did not complete the trial due to drug side effects. In addition, of the 86% of patients on long term STI571 treatment, 75% achieved either complete or major cytogenetic responses (Mauro and Druker). Not only did blood counts return to normal, but in many cases the molecular causative agent of disease, the Philadelphia chromosome, had become undetectable. These results were also observed in the 233 accelerated phase patients: 91% achieved a hematologic response, 41% had a cytogenetic response, and mean survival at one year was 74% (Mauro and Druker). In blast crisis patients, typically the most difficult group to treat, 64% of the 260 patients achieved either a hematologic or cytogenetic response while the median survival of 6.8 months compared favorably with the 3 month median survival for bone marrow transplant recipients (Mauro and Druker). As a result of its clear clinical benefits for the treatment of CML, in May 2001, after a mere three months of review, the FDA approved STI571 for general use under the trade name of Gleevec. The speed of this decision reflects the amazing significance of Gleevec's application for the treatment of an often fatal disease.
Looking to the Future
As a chemical agent, Gleevec clearly represents an important advance in the field of cancer therapy. It has minimal side effects, mostly limited to mild nausea and edema without involving the major systemic toxicity and organ-targeting common to many chemotherapy agents. The drug can also be taken orally, which not only frees the patient from the painful process of repeated intravenous administration of chemicals but also eliminates the requirement for hospital admission. In research applications, Gleevec's specific targeting and almost unbelievable elimination of cancerous cells represents solid support for rational drug design programs. In addition, it provides a much-needed infusion of hope for a field that can often seem hopeless, particularly in light of the dreams of a "cure for cancer" which have yet to be truly realized.
Despite Gleevec's enormous significance and established clinical benefits, it is still not a complete panacea. There have been reports of CML cases with established Gleevec resistance (Marx). As with other forms of therapy-resistant cancers, additional research is necessary to maximize the efficacy of CML treatment. In one possible improvement, Gleevec is being combined with existing therapies in an attempt to circumvent the drug resistance problem (Marx). Further studies are needed to determine Gleevec's long term health effects on patients as well as its effects on the cancer itself. The drug is still so new that it is uncertain how long the remarkable therapeutic effects will persist. In many CML patients, Gleevec treatment results in an apparent partial or complete elimination of the abnormal Philadelphia chromosome. It is unknown whether cessation of drug treatment will result in a recurrence of the bcr-abl fusion. In addition, while Gleevec is a spectacular example of the power of molecular targeting, it does have a distinct advantage in that CML is almost unilaterally caused by a single molecular event. Most other cancers are far more complex. The true utility of molecular targeting will be tested in the development of therapies to treat cancers resulting from multiple molecular aberrations.
Yet even in this arena Gleevec may still prove useful. While the complete ramifications from clinical studies are pending, Gleevec's kinase inhibitory abilities have been tested against the c-kit and PDGF kinases. C-kit and PDGF mutations are known to be a part of the progression of certain kinds of gastrointestinal, prostate, and lung cancers as well as glioblastoma, an aggressive form of brain cancer (Mauro and Druker).
Cancer's molecular complexities and devastating consequences ensure that oncology research will remain a challenging and vitally important intersection of medicine and basic science. Researchers and clinicians must continue to effectively utilize new laboratory techniques, experimental knowledge, and clinical evidence in the advancement of cancer therapy. Gleevec's fundamental contribution to this process is the validation of rational drug design. As illustrated so clearly in the treatment of CML, molecular targeting can be used to effectively treat cancer. In the words of Dr. Richard Klausner, the director of the National Cancer Institute: "Gleevec offers proof that molecular targeting works in treating cancer, provided that the target is correctly chosen. The challenge now is we've got to find these targets." Gleevec's legacy is most clearly seen in a new direction of cancer research: the quest for molecular targets.
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