Bruce A. Chabner, MD, and His Innovative Pharmacology Research Led to the Development of Practice-Changing Therapies

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Bruce A. Chabner, MD

We can now get a drug into the clinic and see results immediately, sometimes after a phase I trial; the FDA accelerated approval system didn’t exist back then. So the tradeoff of today’s extra paperwork burden is well worth it in the long run.

— Bruce A. Chabner, MD

Numerous challenges and milestones mark the course of an oncology career. Community doctors remember special patients, often speaking about a singular bond that is unique among a profession that deals with life and death daily. Researchers recount long hours of seeming futility and then the inexplicable moment of a breakthrough that leads to a new compound. Doctors who move into government and leadership roles in academic institutions need abundant skills to finesse the complexity into a core mission. And there are oncologists who selflessly venture to the poorer regions of the globe to deliver care to the most vulnerable of cancer patients. Then there are the select few whose career is a composite of all of the above. One such remarkable oncologist is Bruce A. Chabner, MD.

Dr. Chabner grew up Shelbyville, Illinois, a small farming community in the center of the Prairie State. “My father was a general practitioner in Shelbyville, which was a beautiful little town that I still visit frequently. My dad’s practice was based on whatever the needs of his patients were, from delivering babies to fixing broken bones and appendectomies. In the later part of his career, he focused on internal medicine. His practice had a lot of influence on my becoming a doctor,” said Dr. Chabner.

Dr. Chabner continued, “I left Shelbyville after my third year of high school and went to Yale University, first with the intention of majoring in biology. But I became very interested in history and spent the majority of my junior and senior years in the history department, with a focus on modern European history and the territorial settlements of the Paris Peace Conference of 1919. Although I changed direction, my time in history was valuable, primarily because I learned to write.”

Early Career in Drug Development

After graduating summa cum laude from Yale in 1961, Dr. Chabner decided to follow in his father’s medical footsteps and entered Harvard Medical School. “I was very interested in pharmacology, which would help later on in my research career,” said Dr. Chabner. He graduated from Harvard, earning his MD degree in 1965, and then completed house staff training at the Peter Bent Brigham Hospital. In 1967, at the height of the Vietnam War, Dr. Chabner joined the National Cancer Institute (NCI) as a clinical associate. Serving at the NCI was an attractive alternative to military service and would also be a pivotal point in his career.

“As I was getting ready to leave for the National Institutes of Health (NIH), my sister was diagnosed with a malignant thymoma. That event solidified my decision to pursue a career in oncology,” said Dr. Chabner.

“The NIH was the most active place in the country to learn about cancer drug development and early-phase clinical trials. I spent 2 very formative years in the clinical service under the tutelage of Drs. Vince DeVita and George Canellos. I had a wonderful time there, learning about cancer, lymphomas, and experimental therapeutics. That’s when I really became interested in biochemistry and biochemical pharmacology, learning how drugs worked and how drug resistance develops,” said Dr. Chabner.

Methotrexate Research

Although methotrexate has been used for more than 40 years, Dr. Chabner’s early pharmacologic research was essential for the full development of this agent as a clinically useful drug. “I left the NIH in 1969 and returned to Yale University to finish my residency. Then I spent a year in the pharmacology laboratory of Dr. Joseph Bertino, learning about enzymology and biochemistry. We purified and characterized an enzyme called carboxypeptidase, which cleaves folates. Although carboxypeptidase was originally conceived of as a treatment by way of folate depletion, it actually found another place in medicine as a rescue agent for methotrexate. It is now approved for cleaving methotrexate in patients who have drug toxicity related to high-dose regimens, and was the first bacterial enzyme to be used therapeutically,” said Dr. Chabner.

In 1971, Dr. Chabner returned to the NCI as a Senior Investigator in the Laboratory of Clinical Pharmacology, where, among other research efforts, he continued investigations in the field of antifolate drug resistance. “At NCI, I immediately became involved in research related to the mechanism of activation and determinants of response related to antimetabolites, and in particular, the biochemistry of cytosine arabinoside. I continued to be interested in antifolates, particularly in the activation to polyglutamates and the pharmacokinetics in high-dose therapy, and developed a method for monitoring drug levels. It is still used as standard part of high-dose methotrexate therapy,” said Dr. Chabner.

Dr. Chabner moved his discussion from the lab to the clinic. “We became very interested in non-Hodgkin lymphoma, and under Vince DeVita’s guidance, we developed active combination chemotherapy regimens. Most of the regimens have changed, but the basic principles of combinations and the curability of the disease set the foundation for what we have today,” said Dr. Chabner.

Transformative Period at the NCI

In 1980, Dr. Chabner was named Associate Director of the Clinical Oncology Program and in 1982 succeeded Dr. DeVita as Director of the Division of Cancer Treatment. “The Division was responsible for intramural research, as well as the intramural clinical trials program, the NCI’s cooperative group program, grants related to clinical trials, and drug development,” Dr. Chabner said.

During this very busy period, several important drugs were coming through the system, he confirmed. “One was cisplatin, which was being tested in a variety of diseases in cancer centers and the NCI’s cooperative group. The second compound of great interest was paclitaxel. It was discovered on contract with the NCI and presented a rather unique situation. There was no intellectual property patent for the taxanes. We had a lot of key data on its activity and use in the clinic, however, and we licensed it through a rather unique contract mechanism to Bristol-Myers. This became an important turning point in drug development because it became the first billion dollar cancer drug and that attracted the attention of the pharmaceutical industry,” said Dr. Chabner.

He continued, “The other area of great interest while I was at the NCI was in AIDS and AIDS drug development. Robert Gallo had isolated the virus that causes AIDS and developed the blood test to detect the virus in the division of cancer treatment. Then Sam Broder developed a screening system and discovered the first drug that was effective against HIV: AZT. AIDS drug development became an important part of our mission at NCI.”

After more than 27 years at the National Cancer Institute and 13 years as the Director of the NCI’s Division of Cancer Treatment, Dr. Chabner left the NIH in April 1995 to accept a new position at the Massachusetts General Hospital (MGH). “Since coming to Boston, I’ve been involved in much of the same kind of research activities that were pursued at the NIH. However, when I first arrived at MGH, we had the challenge of building a clinical service. I did that in partnership with the other Harvard hospitals and the Dana-Farber Cancer Institute. I was fortunate that a lot of talented people came to MGH in my early days there, working with Daniel Haber, Tom Lynch, David Ryan, Jeff Engelman, and many others,” said Dr. Chabner.

Drug Development Then and Now

Asked to contrast the research environment of the NCI with the current setting, Dr. Chabner responded, “Well it was very easy back then to take an idea into the clinic and write a protocol and to quickly get it implemented into a study. There were very few barriers to conducting clinical research, and there was so much to learn. However, the U.S. Food and Drug Administration (FDA) was rather skeptical and slow at approving new cancer drugs in those days. So on one hand today’s review system is more complicated on the administrative side, but on the other hand we have a more receptive FDA, which is partnering with industry and academic centers to advance more compounds through the pipeline.”

He added, “We can now get a drug into the clinic and see results immediately, sometimes after a phase I trial; the FDA accelerated-approval system didn’t exist back then. So the tradeoff of today’s extra paperwork burden is well worth it in the long run.”

Notable Achievements

Despite the demands of a long career, Dr. Chabner shows no signs of slowing down. “I’m currently the emeritus director of the MGH Cancer Center and have very limited administrative responsibilities. I’m involved in a large community outreach program sponsored by the Lazarex Cancer Foundation. I’m also part of an outreach program to establish cancer treatment and control services in Botswana.”

He continued, “I lecture, teach, mentor fellows, and attend on the medical service. I have more time now for writing and for interacting with colleagues in industry and the government on drug development issues. Over the years, Boston has become an international center for cancer drug development, both in biotechnology and large pharma.”

Over the course of his notable career, 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, the Melville Jacobs Award of the American Radium Society in 1986, the Bruce F. Cain Memorial Award of the American Association for Cancer Research (AACR) in 1998, and most recently, Fellowship in the Academy of the AACR in 2015.

Dr. Chabner was promoted to the flag rank of Rear Admiral in the Public Health Service (PHS) in 1991. He has received numerous public health awards and medals, including its highest award, the Distinguished Service Medal, which was awarded for his contributions to the development of paclitaxel.

Dr. Chabner, a lifelong golfer, hits the links whenever there’s a weather-permitting window in his exhausting schedule. His favorite partners are his wife, Davi-Ellen (of 51 years), and mentor and fellow researcher, Dr. Joe Bertino, and Dr. Jay Loeffler, Chief of Radiology at MGH. He has what he describes as a terrific family: “Two wonderful children and their spouses, and five grandchildren are a lot of fun,” he said—the rewards of a life well lived. ■