September 17, 2009 — The 2009 Lasker-DeBakey Clinical Medical Research Award will be presented to 3 researchers for their role in developing novel therapeutic agents to treat chronic myeloid leukemia (CML).
Considered the most prestigious medical research award in the United States, this year it will honor Brian J. Druker, MD, from Oregon Health & Science University in Portland; Nicholas B. Lydon, PhD, formerly of Novartis; and Charles L. Sawyers, MD, from Memorial Sloan-Kettering Cancer Center in New York City.
 |
| Dr. Brian J. Druker |
The research conducted by Drs Druker and Lydon led to the development of imatinib (Gleevec, Novartis), the first successful molecularly targeted small-molecule drug approved for cancer therapy. The work of Dr. Sawyers has been critical in defining the mechanisms of resistance to imatinib, which occurs in some patients, according to the award citation. Dr. Sawyers' work ultimately led to the development of a second generation of drugs against CML, which now include dasatinib (Sprycel, Bristol-Myers Squibb) and nilotinib (Tasigna, Novartis).
Imatinib essentially changed CML from a fatal disease into a chronic and manageable condition.
 |
| Dr. Nicholas B. Lydon |
"Over 80% of patients treated with imatinib in the chronic phase remain stable after 5 years of treatment, which means that they achieve remission of their disease," said Maria C. Freire, PhD, president of the Albert and Mary Lasker Foundation, which issues the awards.
"The impact of the work of Druker, Lydon, and Sawyers is enormous because it has given hope to thousands of CML patients around the world, and it is a potential model for the further development of molecularly targeted treatments of disease," she added.
A Short History of Imatinib
The development of imatinib as a therapeutic agent for CML actually began decades ago, and can be attributed to scientific discoveries that involved a number of researchers. Almost 50 years ago, Peter C. Nowell, MD, from the University of Pennsylvania in Philadelphia, and David Hungerford, PhD, from Fox Chase Cancer Center in Philadelphia, described a consistent chromosomal abnormality in patients with CML. As technology improved, the chromosomal abnormality was determined to be a shortened chromosome 22. In 1973, Janet Rowley, MD, from the University of Chicago in Illinois, identified the shortened chromosome as being the product of a reciprocal translocation between the long arms of chromosomes 9 and 22.
This became known as the "Philadelphia chromosome;" it was the first time that a consistent chromosome abnormality had been detected in any type of malignancy. Oncogenic mapping showed that the protein tyrosine kinase c-ABL, normally found on the long arm of chromosome 9, had been translocated to chromosome 22 in CML patients. This eventually led to the identification of the BCR-ABL fusion gene and its corresponding protein, which show enhanced tyrosine kinase activity. The leukemogenicity of BCR-ABL was confirmed in 1990 by several researchers, establishing BCR-ABL as a leukemic oncogene (Blood. 2008;112:4808-4817).
As these results began to emerge, both Dr. Druker and Dr. Lydon became intrigued with the idea of a therapy that would target the BCR-ABL protein. Dr. Lydon, then working as a biochemist at Ciba-Geigy Pharmaceuticals (now Novartis, created in 1996 through a merger with Sandoz), helped develop the company's tyrosine kinase inhibitor program in 1986.
In 1993, Dr. Druker set up his own laboratory at Oregon Health & Science University, with the goal of developing a BCR-ABL kinase inhibitor for clinical use in CML patients.
There was no proof of this concept, and the field was waiting for this proof of concept.
Dr. Druker was convinced that it was possible to develop a therapy that would target the molecule causing CML. "But there was no proof of this concept, and the field was waiting for this proof of concept," he said in a video interview produced by the Lasker Foundation. "It just hadn't been done before."
He soon teamed up with Dr. Lydon and other researchers at Ciba-Geigy, and imatinib ultimately emerged as the dominant compound slated for preclinical development, based on its selectivity against CML cells in vitro. The compound possessed pharmacokinetic and formulation properties that made it a suitable candidate for development as a therapeutic agent.
There was, however, skepticism that a tyrosine kinase inhibitor would be effective in the treatment of CML. "My vision, based on the pathogenetics of CML, was that if you came up with a small-molecule drug that would specifically bind to this protein, and not the other proteins that use the same mechanism, you would be able to address the disease," Dr. Lydon said in the video. "That was quite a challenge at the time; most people felt that you needed a cytotoxic drug, because those were the only ones that would work."
The challenge of "how to get a selective compound that would address this defective oncogene" was "quite daunting," Dr. Lydon explained.
In a highly successful series of preclinical experiments, imatinib suppressed the proliferation of BCR-ABL-expressing cells both in vitro and in vivo. For instance, it almost completely (92%–98%) reduced the number of BCR-ABL colonies formed in assays of peripheral blood or bone marrow from patients with CML (J Clin Invest. 2000;105:3-7). Based on these encouraging preliminary results, a phase 1/2 study was designed to evaluate tolerability and the pharmacokinetic properties of the compound and to assess any early signs of efficacy.
Despite the early success, imatinib still faced a number of challenges before clinical trials would begin. These included concerns about toxicity and whether targeting a single kinase would actually prove to be an effective strategy, and convincing a pharmaceutical company to invest in developing a novel agent that would benefit such a small patient population.
"I knew that we had something," said Dr. Druker, and he was eventually able to convince Novartis to move the compound into clinical trials.
The project had its ups and down, and I was holding my breath.
 |
| Dr. Charles L. Sawyers |
"The project had its ups and down, and I was holding my breath," added Dr. Lydon.
In June of 1998, imatinib finally moved into phase 1 trials, in a collaborative effort that involved teams led by Dr. Sawyers. The results were "remarkable." At doses of 300 mg or greater, 98% of chronic-phase patients who had failed standard therapy achieved a complete hematologic response, with only 1 relapse reported after 1 year. Among patients in myeloid-blast crisis, 55% treated at the same dose also responded, with 18% having responses lasting beyond 1 year (Blood. 2008;112:4808-4817).
The large-scale phase 2 and 3 trials that followed continued to demonstrate the efficacy of imatinib in treating chronic-phase CML. These data resulted in imatinib receiving accelerated approval by the US Food and Drug Administration (FDA) on May 10, 2001.
Resistance to Imatinib and the Next Generation
The researchers were soon faced with another challenge. Approximately 10% to 15% of patients were apparently developing resistance to the drug and experiencing relapses or progressing to accelerated phase or blast crisis within a year.
"We began seeing a pattern of relapse in the blast-crisis patients and we began to wonder: What is changing in these patients' tumor cells that is causing the resistance to develop?" Dr. Sawyers said in the video. "The upshot of that is that we discovered that most of these patients had new mutations."
Dr. Sawyers and his colleagues were able to make a major breakthrough in 2001 by identifying T315I mutations that were present in patients who relapsed on imatinib therapy. It was also recognized that at least half of all patients who do relapse with imatinib have BCR-ABL point mutations in at least 40 different amino acids that are dispersed throughout the ABL kinase domain (Blood. 2008;112:4808-4817).
Understanding the mechanism of resistance to imatinib led to the rapid development of second-generation BCR-ABL inhibitors, which were able to effectively circumvent resistance. Now, both dasatinib and nilotinib are FDA-approved for patients with resistance or intolerance to imatinib.
Because imatinib has also been shown to inhibit the platelet-derived growth-factor-receptor and KIT tyrosine kinases, its clinical indications have been expanded. Imatinib has been used in the treatment of gastrointestinal stromal tumor, which is primarily driven by KIT mutations, and it has also shown significant activity in patients with acute lymphoblastic leukemia with BCR-ABL-positive disease. Significant responses to imatinib have also been observed in a subset of patients with chronic myelomonocytic leukemia and with hypereosinophilic syndrome.
Future Nobel Prize Winners?
The Lasker Awards are often seen as a precursor to the Nobel Prize; 76 Lasker laureates have received the Nobel Prize, including 28 in the past 2 decades. In addition to the Lasker-DeBakey Clinical Medical Research Award, 3 other awards are being presented: the Albert Lasker Basic Medical Research Award, the Mary Woodard Lasker Public Service Award (renamed in 2000 from Albert Lasker Public Service Award), and the Lasker-Koshland Special Achievement Award in Medical Science.
The Lasker Awards will be presented at a ceremony on Friday, October 2, at the Pierre Hotel in New York City, and carry an honorarium of $250,000 for each category.
Medscape Medical News © 2009 Medscape, LLC
Send press releases and comments to news@medscape.net.
Cite this: Lasker Awards Honor Leukemia Researchers - Medscape - Sep 17, 2009.
Comments