PHILADELPHIA—Fifty years after Peter Nowell, MD, and David Hungerford, PhD, discovered the genetic abnormality associated with chronic myelogenous leukemia (CML) known as the Philadelphia chromosome, the milestone scientific achievement that also led to the development of the first targeted therapy for cancer was celebrated at a one-day symposium here in the birthplace of the finding.
“The discovery of the Philadelphia chromosome revolutionized cancer, research in general, and in particular laid the foundation for modern cancer cytogenetics,” said Felix Mitelman, MD, PhD, Professor in the Department of Clinical Genetics at the University Hospital, Lund, Sweden, speaking at the event, titled “Philadelphia Chromosome Symposium: Past, Present, and Future,” which was sponsored by Fox Chase Cancer Center.
“Like all important discoveries, though, it also opened Pandora's Box, leading to the inscription of an enormous amount of chromosome aberrations in different kinds of human cancer and leukemia.”
A 50-Year Perspective
In addition to Dr. Mitelman, who maintains a database of nearly 60,000 cases of chromosome aberrations in neoplastic disorders, the symposium featured presentations by several other researchers who were instrumental in furthering understanding of the Philadelphia chromosome over the last half century.
Dr. Nowell, the Gaylord P. and Mary Louise Harnwell Emeritus Professor of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine, discussed how he and Dr. Hungerford, then a graduate student at Fox Chase, who died in 1993, detected the genetic abnormality on chromosome 22, naming it after the city in which they both worked.
“The Philadelphia chromosome represents the dream that every researcher has to make a dramatic difference in patients' lives,” Fox Chase President and CEO Michael V. Seiden, MD, PhD, said in a news release. “The fact that David Hungerford was a student early in his career at the time of the discovery reminds us that scientists at every stage can—and do—make significant contributions.”
Also speaking at the event were:
- Janet D. Rowley, MD, the Blum-Riese Distinguished Service Professor of Medicine at the University of Chicago, who discussed her characterization of the Philadelphia chromosome as a translocation between chromosomes 9 and 22 in 1973.
- Nora C. Heisterkamp, PhD, now a Professor in the Division of Hematology-Oncology at the USC Keck School of Medicine, who, since 1981, worked proving Dr. Rowley's claim, identifying the BCR and ABL genes which become fused as a result of the chromosomal translocation.
- Owen N. Witte, MD, Howard Hughes Medical Institute (HHMI) investigator and Professor of Microbiology, Immunology, and Molecular Genetics at UCLA, who talked about his use of mouse models to define the ABL tyrosine kinase in mice and humans.
Crucial to the story of the Philadelphia chromosome was the discovery of imatinib (Gleevec), the first targeted therapy for cancer, which directly resulted from the pioneering research being celebrated. Nicholas B. Lydon, PhD, of Granite BioPharma LLC, Jackson Hole, WY, who discovered the agent along with Brian Druker, MD, Director of the Oregon Health and Science University Knight Cancer Center, discussed the development of preclinical imatinib and the impact they expected it to have in CML.
Initially, though, as John M. Goldman, DM, explained, Novartis had no interest in making imatinib in clinically relevant quantities because they thought CML was a very rare disease.
“We were horrified by the negative attitude, said Dr. Goldman, Senior Research Investigator at Imperial College London, UK. “Patients petitioned, there were multiple efforts from the medical profession as a whole, and I wrote a letter personally to the chief executive officer hoping to dissuade him to become more positive. The efforts were in fact successful.”
In 2001, the FDA approved imatinib for the treatment of CML and the news exploded in both the media and the medical community, added Charles L. Sawyers, MD, HHMI investigator and Chairman of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center. “In just 10 years we've already come so far with this agent.”
Ph+ CML Today
Speaking on the future of tyrosine kinase inhibitors (TKI) in CML, Dr. Goldman said, “We have at least as many unanswered questions as those we've answered in the last two decades.”
The most prominent issue is overcoming resistance to imatinib. Regarding the second- and third-generation TKIs nilotinib, dasatinib, and bosutinib, Dr. Goldman said the question often asked is whether the available data can be used to choose one of these new agents as a treatment for patients who have failed to respond to imatinib.
“The answer is possibly, but not certainly. There is little to choose between efficacy with nilotinib, dasatinib, and bosutinib for a patient who has failed imatinib, and all three agents are ineffective against the gatekeeper mutation in the kinase domain.”
Regarding the question of using one of these agents based on toxicity, Dr. Goldman added that this choice is not clear-cut either.
“Bosutinib is quite good at producing diarrhea, dasatinib causes pleural effusion and myelosuppression, and QTC prolongation in all three agents is quite uncertain. I don't think there is any clear indication of which tyrosine kinase inhibitor should be used. A decision might best be made using availability.”
While resistance to imatinib has been a relatively rare event, the field is learning from those patients for whom the treatment has not worked, said Jeff Boyd, PhD, Executive Director of the Institute for Personalized Medicine at Fox Chase, in an interview following the symposium.
“In the space of targeted cancer therapy, the story of imatinib and CML is a truly incredible success by any standard. We are learning from those patients for whom therapy is not a success and this gives us insight into cancer biology and gives us information that we'll be able to use for other targeted therapies for other cancers. It's very instructive, not just in the context of CML, but in targeted therapy generally.
“For any disease, the field never rests. The Biomedical Research Committee is constantly looking for ways to improve therapies for diseases that we are currently successful at treating because you can always find a drug that's more efficacious, that's effective at a lower dose, has fewer side effects, and that's what we're talking about in this particular case.
“I think a decade from now we'll probably no longer be using imatinib to treat CML; there will be a host of second- and even perhaps third-generation drugs that are found to be more efficacious at lower doses.”
Funding for the symposium, Fox Chase noted, came partly from Novartis as well as from MetaSystems.
Philadelphia Chromosome Day! In recognition of the discovery of Drs. Nowell and Hungerford, Donald Schwarz, MD, Deputy Mayor of Health and Opportunity and Health Commissioner for the City of Philadelphia presented Fox Chase with an official proclamation from Mayor Michael Nutter declaring Sept. 28, 2010 Philadelphia Chromosome Day.