There is a theme running through the work of Larry Norton, MD, of Memorial Sloan-Kettering Cancer Center: quantitative, mathematical approaches to studying cancer. His goal is to better understand the growth patterns of these diseases and thereby plan optimal treatment with established and novel drugs, focusing on breast cancer. This approach has led Dr. Norton and his collaborators to broadly influence cancer therapy for many decades. Some of the ideas that have been influenced by this work include giving treatments often, rather than infrequently, at high-dose levels; the sequential use of combinations and single agents, when appropriate; simultaneous rather than sequential use of combinations of chemotherapy with molecularly targeted therapies; and the use of drugs and intermittent scheduling to overcome feedback mechanisms of resistance.
For these among other contributions, Dr. Norton has been named the recipient of the 2013 Gianni Bonadonna Breast Cancer Award and Lecture. His lecture, titled “The Co-Evolution of Clinical and Basic Science in Oncology,” will be presented Sunday, 10:00 AM-10:45 AM (PDT). The award, first presented in 2007, recognizes an active clinical and/or translational researcher with a distinguished record of accomplishments in advancing the field of breast cancer.
The Concepts of Dose Density and Self-Seeding
As a clinical oncologist, Dr. Norton has spent his career exploring why some patients are helped enormously by drug therapy while others have not benefitted from such treatments. His goal has always been to maximize the benefits of treatment while minimizing toxicities, which seemed to him early in his career to be an engineering problem. He recognized that engineering requires a mathematical understanding of a process, which in this case is tumor growth. During the 1970s in collaboration with Richard Simon, Sc.D., at the National Cancer Institute, Dr. Norton used experimental data to formulate the Norton-Simon Hypothesis, which states that the rate at which a cancer shrinks in response to therapy is proportional to its growth rate: faster growth means faster shrinkage, and slower growth means slower shrinkage. Since the growth rates of cancers vary depending on their size, this led directly to the concept that effective doses of drugs need to be given often— “dose density”—which conflicted at that time with the idea that giving very high doses was most important.
“A problem that needs to be solved has to do with regrowth of the tumor between cycles of treatment. If you can treat more often with a good dose, you would do better than if you took that same dose or even a higher dose and used it less often,” Dr. Norton explained in an interview with ASCO Daily News. “Another big problem with eradicating cancer is that you have to treat more aggressively when the tumor is below the level of clinical appreciation than when it is above that level.”
Since dose density involves the relationships among dose level, tumor growth rate, the tumor’s rate of shrinkage, and the time interval between doses, a physician cannot make estimations. Mathematics is absolutely required to determine the right dose, interval, and sequence.
According to Dr. Norton, dose density illustrates important factors pertaining to oncology as a whole that must be kept in mind.
“Dose density uses standard agents in a different way,” Dr. Norton said. “It’s not always the next new drug that makes a difference. We may already have the drugs we need to cure cancer now, if we use them properly. Of course, the current availability of molecularly targeted drugs may move us even more quickly to our goals, but still: we have to use them the optimal way.”
Dr. Norton, along with Joan Massagué, PhD, recently advanced this research with the self-seeding hypothesis, which states that cancer cells can take one of five different pathways in the body, spreading not only to distant organs, but circling back to the original tumor site.
“If cells are going back to the tumor, they are going back to the outside of the tumor,” Dr. Norton explained. “Hence, tumors do grow more slowly as they get bigger because they are growing from the outside in rather than the inside out.”
Collaborations and Contributions
Currently, Dr. Norton is focused on developing antimetastatic drugs that interfere with the mobility of the cells rather than just with cell division. Dr. Norton plans to speak on this research and on his previous cancer advances during the Gianni Bonadonna Breast Cancer Lecture. He plans to stress that these discoveries were a collaborative effort and not the brainchild of one person.
“There is no one hero, and it’s certainly not me,” he said. “The greatest joy of my career has been working in collaboration with communities and groups as a coordinated team. As someone once said, ‘There’s no end to what people can accomplish when they don’t care who gets the credit.’ That’s been one of the central principles of my career.”
Dr. Norton’s contributions to cancer extend beyond the laboratory and into government and advocacy. He was a U.S. Presidential appointee to the National Cancer Advisory Board (1999-2004), serving as chair of the Budget Sub-Committee. Dr. Norton served as president of the American Society of Clinical Oncology (2001-2002) and subsequently chair of the ASCO Foundation (2002- 2004), which is now the Conquer Cancer Foundation. Dr. Norton is a founder of The Breast Cancer Research Foundation and is currently its scientific director. For his work, Dr. Norton has received many awards including ASCO’s highest honor, the David A. Karnofsky Award, and was a McGuire Lecturer at the San Antonio Breast Cancer Symposium.