Inside NYP: Lewis Cantley
A world-renowned cancer researcher leads the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center.
Where I grew up in rural West Virginia, almost all families were subsistence farmers. Only a couple of people in my family had gone to college. My mother graduated college in four years while raising four kids between 12 and 4 years old. My father did not go to college but read the entire encyclopedia during the time Mom was in college. This family emphasis on education led me to get a Ph.D. in chemistry, my brothers Larry and Lloyd to become medical doctors and my sister Linda to get a degree in sociology.
I knew I wanted to be a scientist early on. I was greatly influenced by my father, who was a brilliant man. When I was growing up, I would ask him, “Why does it rain?” He would go into great detail about nucleation of water condensation, which caused the clouds, and why they would release rain. He’d learned all that, because he was in the Coast Guard during World War II. He took courses in weather prediction as well as predicting tides. He knew why there were two tides a day rather than one and could explain all of that to a 6-year-old kid. By the time I was 12, I could disassemble and reassemble every part of a tractor or automobile and restore its function. My Christmas presents were things like microscopes or chemistry kits or broken vehicles that needed repair.
I studied chemistry and math at West Virginia Wesleyan College, and my Ph.D. from Cornell University is in biophysical chemistry. After doing postdoctoral research at Harvard, I was offered a position as an assistant professor at Harvard, where I taught biochemistry and biophysical chemistry. I later became a professor at Tufts University and then moved to Harvard Medical School, where I was a member of the cell biology department and also a division chief at Beth Israel Deaconess Medical Center.
As I started my own laboratory in the mid-1970s, I was working on the basic mechanisms by which molecules get into and out of cells: How does that work? How do you get sodium ions or potassium ions out of the cell? How does insulin cause glucose to enter muscle and fat cells? We had no idea. The work would eventually lead to a significant discovery.
It had occurred to me that since cell membranes are made up of lipids, the chemical modification of a lipid might play a role in regulating the transport of glucose or other nutrients or salts across the cell membrane. I began to look for the enzymes that put phosphate groups onto lipids (lipid kinases), and my lab eventually discovered one that was regulated by insulin and other growth factors.
I was in the lab in the spring of 1987 with my graduate student Malcolm Whitman when he showed me a shocking result. The lipid that was being produced by the insulin-activated lipid kinase that we were purifying was not what we had thought it was. We had thought it was producing phosphatidylinositol-4-phosphate (PI4P), a well-known lipid discovered almost 40 years earlier that was known to play a role in cellular regulation. But the lipid produced by the lipid kinase that was activated by insulin could be separated from PI4P by chromatography. We had discovered a completely new pathway for cellular regulation that everyone had missed. To physicists, this would be like finding a quark no one had ever seen before. We toasted with Champagne that evening.
Over the next few months we showed that this enzyme was producing phosphatidylinositol-3-phosphate (PI3P), a molecule that was similar to PI4P but had never been seen before. Over the next few years we went on to show that this enzyme, which we called phosphatidylinositol-3-kinase (PI3K), could generate a family of lipids (PI3P; PI3,4P2; PI3,5P2; and PI3,4,5P3) in response to stimulation of cells with insulin and other growth factors and that these lipids controlled the ability of cells to take up glucose and other nutrients and to use them to grow.
As my lab was uncovering the mechanism by which PI3K mediates insulin responses, we were also collaborating with Tom Roberts’ lab at Dana-Farber, Brian Schaffhausen’s lab at Tufts, and Peter Vogt’s lab at Scripps to characterize the role that PI3K plays in mediating cancer growth by cancer-causing viruses. It had become clear that cancer-causing viruses were using the same mechanism to drive cell growth as insulin: Both converged on activation of PI3K. So I began to suspect even in the 1990s that high levels of insulin might enhance the growth of cancers. Nobody was thinking that. For endocrinologists, insulin is a miracle drug that rescues patients from both type 1 and type 2 diabetes. They have no concern about using this drug, even at super-physiological doses for patients with type 2 diabetes.
Yet epidemiology studies have revealed a correlation between obesity, insulin resistance, diabetes, and increased risk for certain cancers. I began to suspect that the high levels of insulin in the blood of patients with insulin resistance could explain this correlation. We now know that activating mutations in the gene encoding PI3K (PIK3CA) and loss-of-function mutations in a gene that degrades the lipid products of PI3K (PTEN) are the most frequent events in human cancers. Importantly, we knew that these mutations allow insulin to activate PI3K more readily. So while the liver and muscle in a patient with insulin resistance do not respond to insulin, the cancer cells are hyper responsive to insulin.
Although we have made a lot of progress in understanding the role of PI3K in insulin signaling and cancers over the past 30 years, it was not always smooth sailing. There was considerable skepticism of our claim in the 1980s that a lipid kinase was activated by cancer-causing genes. Most researchers in this field were virologists or molecular biologists and had little or no experience working with membrane lipids. The leading laboratories in the field published papers arguing that our findings were not correct, and this made it difficult to publish our work or obtain grants to support it. The graduate students from my lab and Tom Roberts’ lab, Malcolm Whitman and David Kaplan, visited a few of the skeptical scientists and showed them how to do the lipid kinase assay. After that, they were able to reproduce our results and became supporters of the discovery. The lipid chemists were also skeptical that they could have missed this family of lipids over more than 30 years of research, but they ultimately were able to reproduce our results. Yet there were three to four years when funding and publishing this work was difficult.
Figuring out all the cellular events controlled by the PI3K-generated lipids is ongoing. Thirty years later, there’s much more to be discovered. We know a lot — the broad strokes, the major players — but there’s still a lot of subtleties to how this signaling network is regulated and what goes wrong in diseases such as diabetes and cancers.
Cancer tells us a lot about how it works, because mutations that arise are almost invariably affecting some step in growth regulation. By just looking at all the mutations in cancers, we can begin to make sense of it.
As I noted, the gene encoding PI3K, PIK3CA, is the most frequently mutated oncogene across all types of cancers and particularly in women’s cancers. Approximately 30% of breast cancers and 50% of endometrial cancers have PIK3CA mutations.
In 2009, an organization called Stand Up To Cancer, in affiliation with its scientific partner, the American Association of Cancer Research, issued a proposal to fund what they call “dream teams.” At that time I was at Beth Israel Deaconess Medical Center, associated with Dana-Farber Cancer Institute, and I put together a dream team of world-renowned cancer researchers from major institutions throughout the country, including Dr. Ramon Parsons, then at the Herbert Irving Comprehensive Cancer Center at Columbia and NewYork-Presbyterian. We were awarded more than $12 million to evaluate the use of PI3K inhibitors for treating women’s cancers. We went to pharmaceutical companies that were developing these drugs and said, “We can help you design the trials that are more likely to get your drug approved.”
We played a role in designing the phase Ib trial for a Novartis drug called alpelisib for estrogen receptor-positive breast cancer. Forty percent of the patients with these cancers have mutations in PIK3CA.
Along the way we had to resolve issues related to the enzyme’s dual roles in insulin signaling and cancer. If you give a PI3K inhibitor, it hits the enzyme not only in the tumor but also in the liver, muscle, and fat cells, promoting insulin-resistance and diabetes. Being aware that high insulin levels could further activate PI3K in the tumor and drive tumor growth, we insisted that patients on PI3K inhibitors not be given insulin or other drugs that increase insulin production in the pancreas.
Eating a very low carbohydrate diet — limiting both sugar and starch — could be a way to improve responses to these drugs. In studies where we gave a PI3K inhibitor to mice engineered to develop pancreatic, bladder, endometrial, and breast cancers, we put them on a ketogenic diet and their tumors melted away.
Our recent studies revealed that a ketogenic diet, which maintains low levels of glucose and insulin in the blood due to limited carbohydrate consumption, can enhance the ability of PI3K inhibitors to kill tumor cells in mouse models of human cancers. The PI3K inhibitor alpelisib (brand name Piqray) that our dream team evaluated in phase I studies was recently approved by the U.S. Food and Drug Administration for PIK3CA mutant breast cancers, and we are collaborating with Novartis to evaluate the ability of a ketogenic diet to improve responses to this drug.
We are also working on developing a vaccine against breast cancers caused by mutations in the BRCA genes, which confer a significantly higher risk for breast and ovarian cancers. We hope to identify novel proteins in tumors — proteins that aren’t in normal cells — in order to create preventive or therapeutic vaccines, in effect destroying a cancer early, before it’s even recognized as a cancer.
When I came back to Weill Cornell Medicine in 2012 to lead the Sandra and Edward Meyer Cancer Center, I was motivated by the opportunity to build a cancer center in an environment of one of the top medical schools in the country (Weill Cornell Medicine) and the top hospital in New York (NewYork-Presbyterian) where basic scientists and clinicians were really interested in collaborating. One of the biggest challenges at most institutions is that people don’t communicate with specialists outside of their areas. We are bringing together researchers in various fields — basic scientists, pathologists, surgeons, radiologists, oncologists, endocrinologists, epidemiologists, and others.
Through the Tri-Institutional Therapeutics Discovery Institute, a joint effort between Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, and The Rockefeller University, with Takeda Pharmaceutical Co., we are translating early-stage research discoveries into treatments. We can go to their team and say, “We have a validated target; can this be made into something that can be used in the clinic?” That step is rarely taken in academia, but here we’ll be set up to allow that to happen.
My goal is to create a team of people working from bench to bedside and bedside back to bench who interact and have the resources needed to make things happen. By working more closely with our counterparts at Columbia, which is also affiliated with NewYork-Presbyterian, we can more rapidly develop clinical trials that can convert these new discoveries into new cancer treatments. At this point in my career I want to be able to see things that were discovered in my laboratory or in other laboratories at Weill Cornell Medicine and Columbia get converted into new therapies to benefit patients.
Lewis Cantley, Ph.D., is the director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center. He obtained a Ph.D. in biophysical chemistry from Cornell University in Ithaca in 1975 and was a professor at Tufts University and Harvard University in Boston before moving to New York City. He is a member of the National Academy of Sciences and the National Academy of Medicine. He has received a number of awards for his discovery of PI3K and its role in insulin function and in cancer, including the 2000 Heinrich Wieland Preis for Lipid Research, Munich; 2005 Pezcoller Foundation-AACR International Award for Cancer Research; 2009 Rolf Luft Award for Diabetes & Endocrinology Research, Karolinska Institutet, Stockholm; 2013 Breakthrough in Life Sciences Award; 2015 Canada Gairdner International Award, Toronto; 2015 Ross Prize in Molecular Medicine; 2016 Wolf Prize in Medicine, Tel Aviv; and most recently the 2018 Louisa Gross Horwitz Prize from Columbia University.
Dr. Cantley has been a paid consultant for Novartis, and has received research support from Stand Up To Cancer.