Faculty Feature: Dr. Lewis Cantley

For this newsletter’s Faculty Feature, Annalise Schweickart (SVG President), Nick Bartelo, and Shakarr Wiggins (SVG Co-chairs of Outreach) had the opportunity to sit down with Dr. Lewis Cantley, Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell. Dr. Cantley received his Ph.D. from Cornell University, and completed a postdoctoral fellowship at Harvard University. In 1978, Dr. Cantley became an assistant professor of Biochemistry and Molecular Biology at Harvard, where he began a career marked by numerous groundbreaking cancer-related discoveries in his research labs, coupled with many successful entrepreneurial feats. Dr. Cantley joined the faculty of Weill Cornell Medicine and New York-Presbyterian Hospital in 2012. In 2016, he was elected the Chairman of the Board of the Hope Funds for Cancer Research. In addition to his academic success, he has created five companies, the most recent being Faeth Therapeutics. He is now returning to Harvard Medical school where his work continues to push the frontier of cancer treatment.

SVG: You and collaborators discovered PI3K over 30 years ago, and you knew about its implications in cancer pathways over 20 years ago. Fast-forward to today: we have numerous PI3K inhibitors and insulin-suppressing diets in clinical trials to treat cancer. What, in your opinion, was the most important step that accelerated the translation of your findings from the lab to a potential therapeutic?

Cantley: I was fortunate to receive $15 million dollars from Stand Up to Cancer AACR to assemble a clinical team to help design clinical trials to facilitate the approval of PI3K-alpha inhibitors for treating breast cancer. We worked with Novartis, primarily to help design Phase 1 trials with the PI3K-alpha inhibitor called Alpelisib, which is now FDA approved with the commercial name PIQRAY®.  In the Phase 1 trials, we found that when PI3K-alpha is inhibited, the patient instantly becomes insulin resistant.  This is because PI3K-alpha mediates essentially all the effects of insulin in liver, muscle and fat.  In order to get PI3K inhibitors approved, we needed to figure out how to manage the insulin resistance and consequent elevation of serum insulin and glucose.

Using mouse models, we explored ways to make the drug work better. We had the same problem with the mice; they became insulin resistant when given alpelisib. So we switched the mice to a ketogenic diet, which is only about 5% carbohydrate, 80% fat, and 12 to 15% protein. This diet was designed to create ketosis, and does so because the glucose level is so low, that the liver starts metabolizing fat in order to make ketones.  Tissues such as the heart and brain can substitute ketones for glucose to maintain function. This reduction in glucose keeps insulin levels low.  Importantly, our mouse studies indicate that high serum insulin can reactivate PI3Kalpha in tumors, in spite of the presence of the PI3Kalpha inhibitor, allowing the tumors to survive. So when we put the mice on the ketogenic diet, the tumors completely disappeared, and the mice were cured!

SVG: How does Faeth change the behavior of food consumption to become an effective therapy? Is there one, or a few, very common recommendations that seem to have the most impact on successful treatment?

Cantley: The company's strategy is to generate every meal for the patient. We actually provide the meals for them. The meals are designed for different types of cancers or cancer therapies. The meals generated at Faeth are really based on the mouse studies; we came up with the same ratio of carbohydrate to protein to fat. We weren't randomly shooting in the dark. Human metabolism has not changed much in several hundred thousand years. A ketogenic diet is what most humans ate 200,000 years ago when we mainly killed and ate other animals because we hadn't cultivated fruits and vegetables.  So low carbohydrate, high fat diets are very well tolerated by humans, especially if the fats are from fish and vegetable oils.  

Also, Faeth gets feedback from the patients in regard to what they like or dislike in the meals provided and adjust the diet to the patient. Faeth gets detailed comments from the patients like, "finished this part of the meal" or "didn't quite like this ingredient in this diet, so can I have something else". In response, Faeth keeps going back and changing the ingredients to please the appetite of the patient, while still trying to keep the ratios of carbohydrate, protein and fat that are needed to keep the insulin levels low. Every week clinicians evaluate serum from the patients to determine whether low insulin and carbohydrate are maintained on the diets. 

SVG: What would be your main suggestions for grad students who want to start companies?

Cantley: Well, it's hard to start companies as a graduate student, unless it's a company that doesn't require a whole lot of investment. You could start a software company, for example, as a graduate student. Bill Gates did that as an undergraduate. In fact, he was using the computers at the Science Center at Harvard as an undergraduate, which were the same computers I was using as a postdoc at that time. He took advantage of the computers at Harvard, started writing software, and started Microsoft.  Starting a software company as a graduate student is rare, but possible.

But to start a biotech/drug company, one needs a lot of pre-clinical data that validates the novel target or technology that forms the basis of the company. One needs to have a rationale, and truly understand the biology and biochemistry behind treating a disease with a given drug. An example is the company Larkspur Health I started with two other scientists, Nathanael Gray and Vijay Kuchroo. Each of us had a different target we identified within our own laboratories that had been highly validated in mouse models for cancer. This whole company was founded on a collection of novel targets that, when inhibited or degraded, made the immune system attack the tumor more efficiently. We identified targets that worked on a much broader set of cancers than the checkpoint inhibitors that have been approved. So we were able to get funding because of highly validated targets, not to mention the fact that each one of us had independently started two or more successful companies before.

SVG: Did you have a mentor who helped you in the entrepreneurial arena and helped you learn the skills you know today?

Cantley: I learned some on my own. However, my wife, Vicki Sato is one of my inspirations. She was a faculty member at Harvard at the same time I was, and she left Harvard to start a diagnostic company around 1984 where she was the CSO. Then she left that company and went to Biogen, where she became CSO. She ultimately moved to Vertex where she became the president. When she retired from Vertex she became a professor at Harvard Business School and taught a course on starting biotech companies.  Several companies from her HBS course became successful.  So she has had a much greater impact on starting and running companies than I.