Portal de Periódicos da CAPES

First person profile: Larry Norton, MD

2019; Wiley; Volume: 125; Issue: 15 Linguagem: Inglês

10.1002/cncr.32393

1097-0142

Carrie Printz,

BRCA gene mutations in cancer

In the mid-1960s, there was no shortage of budding musicians in Greenwich Village, a famed New York City neighborhood and epicenter of the arts. However, folk music lovers who visited the area's coffee houses might recall one talented young man who often played the guitar or alto saxophone or accompanied beat poets on the bongos. Like so many others from that scene, he would go on to establish an iconic career—only he would do so as an oncologist, taking part in the development of several breast cancer drugs and the discovery of the BRCA1 gene. That musician, Larry Norton, MD, now is a senior vice president of Memorial Sloan Kettering Cancer Center in New York City and the medical director of its Evelyn H. Lauder Breast Center. He is the author of more than 350 published articles and the founder and co-scientific director of the non-profit Breast Cancer Research Foundation. He was a US presidential appointee to the National Cancer Advisory Board, and has, among other things, developed a reputation for guiding eager young people along career paths in medicine. However, he recalls how back then, in the 1960s, his own path was still so unformed. Growing up in Nassau County, a suburb of New York City, Dr. Norton assumed that music would consume his life. By the time he was a student at the University of Rochester in upstate New York, and taking classes at its Eastman School of Music, he was used to running off to the city to play music with his friends and rub elbows with the greats. “I was exposed to people like Bob Dylan and so many luminaries—and I didn't realize it was a golden era. It was just my life,” he says. Nevertheless, Dr. Norton began to question whether that path was really right for him—he was also passionate about math and had a burgeoning interest in science—and when he was given the opportunity to go on tour playing music, he knew he had to think hard about his future. A conversation with his friend Ronald Blum on the library steps at the University of Rochester would help to clarify things. Blum, himself a future oncologist, told Dr. Norton about his experiences interning at Roswell Park Cancer Institute in Buffalo, New York, and how exciting it was. “Cancer medicine was before its infancy then,” Dr. Norton recalls. “But I made the choice between music and medicine and applied for a summer fellowship at Roswell Park.” As a child, Dr. Norton did not have any medical or scientific role models. His father was the first member of the family to attend college and went on to become a newspaper editor. However, Dr. Norton says he always felt a strong desire to help others, and medicine seemed to offer an opportunity to fulfill that impulse. Later, an incident during his Roswell Park fellowship helped to confirm that he had made the right decision and cemented his interest in the oncology field for good. In those days, people did not talk about administering drugs to patients with cancer to cure them, Dr. Norton says. So he was amazed when one of the oncologists he worked with introduced him to a female patient who had a large pelvic tumor and said he would be treating her with a new chemotherapy drug, methotrexate, that still is used today. “Over the summer I saw that tumor—this monster that was eating her up—melt away. I saw the skin grow over it, and I saw her pain go away,” Dr. Norton says. “This was just astonishing and almost magical, and I thought, ‘I can't see myself not being involved in this field.’” Although Dr. Norton has devoted the past 4 decades to oncology, he has not left his other interests behind. He continues to play instruments and is known to weave aspects of music and math into discussions of medicine and health. In fact, Dr. Norton's research on cancer medications has shone a spotlight on how math can be used to optimize doses and dosing schedules. In the early 2000s, he worked with Richard Simon, DSc, the now-retired head of the National Cancer Institute's Biometric Research Program and Computational and Systems Biology Branch, to develop a revolutionary mathematical model called the Norton–Simon hypothesis. According to Dr. Norton, it posited that the way clinicians had been administering drugs was wrong; in essence, the theory states that the rate at which cancer will shrink in response to treatment is directly proportional to the tumor's growth rate. That hypothesis has broadly influenced cancer therapy today, but when Dr. Norton first submitted the article to the National Cancer Institute's journal, the reviewers hated it. “One of them said, ‘The best way of dealing with this paper is tearing it up into many pieces to make sure no one ever sees it, and after that wash your hands,’ ” Dr. Norton recalls, with a laugh. Fortunately, one of his mentors, Vincent DeVita Jr, MD, the Amy and Joseph Perella Professor of Medicine at Yale Cancer Center in New Haven, Connecticut, was the journal's editor. He saw the value in the work and decided to publish it. Although Dr. Norton was considering a move into other research areas at the time, the article's acceptance prompted him to remain focused on applying mathematical modeling to improve drug treatment for patients with cancer. Indeed, the article, combined with Dr. Norton's ongoing research, paved the way for a multisite clinical trial in 1997 that demonstrated the effectiveness of using dose-dense sequential therapy to treat patients with breast cancer. The process entails shortening the intervals between chemotherapy cycles by giving individual drugs sequentially at full dose, rather than giving them at lower doses concurrently. In January 2019, The Lancet published the results of a worldwide analysis of 26 randomized clinical trials that tested the delivery method in more than 37,000 patients, further confirming its effectiveness.1 “Over the summer I saw that tumor— this monster that was eating her up— melt away. I saw the skin grow over it, and I saw her pain go away. This was just astonishing and almost magical, and I thought, ‘I can't see myself not being involved in this field.’ ” — Larry Norton, MD According to Dr. Norton, Dr. DeVita has played a pivotal role, not only in his research, but in the type of professional he aspired to become. “Vince was always a great leader and always trying to pave the way for others,” Dr. Norton says. “He was the smartest person in the room, but he would go to meetings and just listen to people.” Similar to Dr. DeVita, Dr. Norton would go on to mentor a number of young clinicians and researchers throughout the course of his career. In fact, if you ask him what he considers to be his proudest achievement in a life filled with them, he points to his efforts to encourage medical professionals just starting out in the field. “It's the extraordinary number of young people I was able to influence who have gone on to do wonderful things,” he says. “It's the mentorship part of my career that fills my heart with the most joy.” Clifford Hudis, MD, chief executive officer of the American Society of Clinical Oncology, counts himself as one of Dr. Norton's mentees and agrees with his assessment. Dr. Norton, he says, advised many people who ascended to leadership positions or made other contributions across the spectrum of cancer research. “He always had an opinion and guidance for everybody, and that's a remarkable legacy above and beyond his scientific contributions, of which there are many,” Dr. Hudis says. “To this day I talk to him every week, sometimes every day, because he gives really good advice.” The next big area of cancer research that excites Dr. Norton is “the weaving together of mathematics with cancer research to understand the pattern of cancer growth,” he says. Toward that end, he has formed the Mathematical Oncology Initiative, an international consortium to bring mathematicians who have never before focused on cancer issues to work jointly with oncology researchers. Israel's Ben-Gurion University of the Negev, well known for its mathematics department, is heavily involved in the effort, along with the eponymous Dr. Larry Norton Institute at Soroka University Medical Center in Be’er-Sheva, Israel. The institute, which opened in 2018, will focus on cancer research. Another area Dr. Norton hopes to advance is “getting great ideas in the lab commercialized and developed to the point where they can actually help people.” Academic institutions do not have the capacity or resources to support this work, he notes. “Probably every 2 weeks I hear a great idea that I know is going to die in the lab,” Dr. Norton says. He has some thoughts on how to develop support for early research ideas. They include tapping into everything from philanthropic ventures to socially responsible for-profit companies, to getting the federal government to offer financial risk protection to investors, much like it does for the banking industry. He is collaborating with Andrew Lo, PhD, the Charles E. and Susan T. Harris professor of finance at the Massachusetts Institute of Technology Sloan School of Management in Cambridge, Massachusetts, to explore potential solutions to the problem. “There are a lot of innovative ways we can organize the business of drug discovery and diagnosis in cancer,” he says. “The biggest hurdle is that we need a better business model.”