A Tribute to Bruce Chabner

Abstract

After more than 25 years at the National Cancer Institute and 13 years as the Director of the {NCI's} Division of Cancer Treatment, Dr. Bruce Chabner left the {NIH} in April 1995 to accept a new position at the Massachusetts General Hospital. This decision followed several months of agonizing contemplation. I think Bruce recognized earlier and more perspicaciously than most that the climate at the {NCI} was about to change dramatically, leaving diminishing opportunities under governmental auspices for the anti-cancer drug discovery and development as well as the clinical research he so loves. Among the many accomplishments of this phase in the career of Bruce Chabner-the preliminary phase of what we assume will be even greater accomplishments as he moves to the private sector-undoubtedly the most meaningful and enduring are the contributions of those whose formative experiences in basic and clinical research came while under his tutelage. One of the key missions of the {NIH's} Intramural Research Program has been the training of the next generation of scientists; as will be demonstrated in this volume, Bruce Chabner has succeeded remarkably in this endeavor. I could think of no better way to honor Bruce Chabner than to gather his students to discuss their own research. Thus, on April 7, 1995, a symposium of Chabner alumni was held in the Masur Auditorium of Building 10. Opening the program was Bruce's own laboratory mentor, Dr. Joe Bertino, whence Bruce's lifelong passion for folate metabolism and methotrexate research. Following Dr. Bertino were his scientific grandchildren, in approximate chronological order of their time studying with Dr. Chabner. As directors of cancer centers, heads of oncology departments, heads of laboratories, and as working scientists and clinicians, each has achieved prominence in clinical oncology and each has maintained a high level of productivity in both laboratory and clinical research. Just as I am certain that Dr. Bertino takes pride in the accomplishments of his pupil, the accomplishments and prominence of these authors, Dr. Chabner's students, reflect their early mentoring and their recent research serve as testament and tribute. Allow me to briefly recapitulate the highlights to date of the career of Dr. Bruce Chabner. He graduated summa cum laude from Yale College in 1961, and from Harvard Medical School in 1965, followed by house staff training at the Peter Bent Brigham Hospital. He first came to the {NCI} as a Clinical Associate in 1967. In 1969 Bruce left the {NCI} to return to Yale University, where he entered the laboratory of Dr. Joe Bertino. Dr. Chabner and Dr. Bertino did pioneering clinical research in the use of leucovorin rescue following methotrexate. In 1971 Bruce returned to the {NCI} as a Senior Investigator in the Laboratory of Clinical Pharmacology, where he continued research in methotrexate pharmacology and began studying mechanisms of resistance to methotrexate. In 1976 he was named the first Chief of the newly created Clinical Pharmacology Branch in the Clinical Oncology Program ({COP).} In 1980 he was named Associate Director of {COP} and in 1982 Dr. Vince {DeVita} asked Bruce to succeed him as Director of the Division of Cancer Treatment. Dr. Chabner has received numerous awards and honors in recognition of his scientific achievements, including the David A. Karnofsky Memorial Lectureship of the American Society of Clinical Oncology in 1985, and the Melville Jacobs Award of the American Radium Society in 1986. Dr. Chabner was promoted to the flag rank of Rear Admiral in the Public Health Service ({PHS)} in 1991. He received numerous {PHS} awards and medals, including its highest award, the Distinguished Service Medal, which was awarded for his contributions to the development of the important anti-cancer drug paclitaxel (Taxol®). Although methotrexate has been used for more than 40 years, Dr. Chabner's early pharmacological research was essential for the full development of this agent as a clinically useful drug. Early in his career, he developed and refined assay methods for determining plasma levels of methotrexate. This work made possible the accurate prediction, based on plasma methotrexate levels, of bone marrow toxicity in patients treated with this drug, and allowed safe clinical use of methotrexate in conjunction with leucovorin. Methotrexate levels are now routinely used to determine the dose and duration of leucovorin treatment necessary to prevent methotrexate toxicity. Dr. Chabner's research group made the important discovery of the intracellular conversion of antifolates to an altered form that inhibits other intracellular enzymes in addition to {DHFR.} This work led to an understanding of certain mechanisms of methotrexate resistance whereby cells lose the ability to modify the drug, and also directly led to the synthesis and clinical testing of drugs specifically targeting the unique enzymes that are inhibited by the modified antifolate drugs. Additionally, the first evidence of gene amplification in a drug-resistant human malignancy came from this group, when {DHFR} was found to be amplified in a patient with small-cell lung carcinoma. Bruce's recent work involves the general phenomenon of multi-drug resistance, as exemplified by Dr. Susan Bates's article in this issue. As Director of the Division of Cancer Treatment ({DCT)} from 1982 through 1995, and as we now know, the last Director of this now-defunct entity, Dr. Chabner became a true leader of a national and international research program whose mission was, simply, to improve the therapy for cancer. Both the {DCT's} intramural preclinical and clinical programs and the diverse country-wide extramural programs supported by the {DCT} made many important advances during these years. Perhaps most exemplary of the importance of his leadership was the story of Taxol® development, important clinical aspects of which are discussed herein by Dr. Ross Donehower. In 1990, the first reports were received by the {NCI} that Taxol®, an anti-cancer drug isolated from the bark of the Pacific yew tree, Taxus brevifolia, was remarkably active in women with refractory ovarian cancer who had been previously treated with platinum compounds. Paclitaxel had been discovered many years earlier, but because of very limited supply of the drug and because of its toxicity in early clinical testing, its development had been very slow prior to these reports. The {NCI} immediately embarked upon a major effort to rapidly increase the supply of the drug to ensure expeditious clinical confirmation of the initial result, to test the drug in a variety of other cancers, to optimize its dosing and scheduling, and to assure wide availability of the drug. Within two years the supply problem was solved, the activity of the drug in ovarian cancer was confirmed, and significant activities in breast cancer and non-small cell lung cancer were found. Taxol® was approved for use, first in ovarian cancer, then in breast cancer, and is now-just five years later-one of the most important drugs in the oncologist's armamentarium. This rapid development project was unprecedented in cancer drug development. Bruce's leadership in organizing and supporting this very complex collaborative effort involving the {NCI}, Bristol-Myers Squibb, the {U.S.} Forestry Service and the Bureau of Land Management was essential to its success. All of this was accomplished in spite of powerful, albeit wrong-headed, political opposition from Capitol Hill. Bruce finessed this brilliantly. In the military, the words "honor" and "duty" are frequently used to describe the career or the individual acts of an officer. Admiral Chabner, in all his endeavors-physician, scientist, teacher, the leader of a national cancer research program-is known among his many friends and colleagues as a man who has conducted his office with highest honor, with scrupulous intellectual and ethical integrity, and in a manner going far beyond the call of duty. His leadership of the Division of Cancer Treatment was born from more than a sense of duty to the office; it grew from his love of and respect for both science and medicine, from the knowledge and experience that came from years in the laboratory contemplating and doing research, and, ultimately, from the desire to improve the lives of patients with cancer. These qualities will assure his continued success at Massachusetts General Hospital. From Advances in Cancer Treatment: The Chabner Symposium. Stem Cells 1996;14:3-4