Topol Talks to Ferrara, $3M Breakthrough Prize Winner

; Napoleone Ferrara, MD, PhD


May 02, 2013

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Editor's Note: In this segment of Medscape One-on-One, Eric J. Topol, MD, interviews molecular biologist Napoleone Ferrara, MD, PhD, whose research on tumor growth led to the development of the cancer drug bevacizumab (Avastin®) and the macular degeneration treatment ranibizumab (Lucentis®). Ferrara recently received a Breakthrough Prize in Life Sciences, which comes with a $3 million award.


Dr. Topol: Hello. I'm Eric Topol, Editor-in-Chief of Medscape. I'm delighted to be here to do a discussion with Dr. Napoleone Ferrara. Napoleone is a Distinguished Professor of Pathology here at the University of California, San Diego (UCSD).

What a record you have had in your career -- not only winner of the Lasker-DeBakey Clinical Medical Research Award and The Economist's 2012 Innovation Award for Bioscience, but most recently the Breakthrough Prize in biomedicine. We're going to get to that Breakthrough Prize because that just happened, but before we do, maybe we'll start off with your obstetrics and gynecology training back in Italy. Can you tell us a little bit about those days in the way past?

Training in Italy

Dr. Ferrara: That was a long time ago -- almost 3 decades ago, actually. I was a medical student in Catania, Sicily. I was very fortunate to have a mentor, a professor of pharmacology, who guided me to do research, and he spent a number of years at the University of California, San Francisco. Through him, I was able to get a fellowship at UCSF.

Before that, I had some clinical training in ob/gyn. I was actually very interested in reproductive endocrinology. That's why I started this research fellowship at UCSF. That's where my career started from that point.

Dr. Topol: What year did you go to UCSF?

Dr. Ferrara: It was early 1983.

Dr. Topol: Then you went from UCSF to Genentech?

Dr. Ferrara: Yes; actually, I did 2 different postdoctoral posts in 2 different laboratories at UCSF, and then in 1988, I joined Genentech.

Discovering Vascular Endothelial Growth Factor

Dr. Topol: When did you discover vascular endothelial growth factor (VEGF)? That's kind of like your middle name, VEGF. How did you get into that whole area?

Dr. Ferrara: That was actually work that I did when I was a postdoc. The whole story began in my initial postdoc with Dr. Richard Weiner in the Department of Obstetrics, Gynecology & Reproductive Sciences at UCSF. I was working on some pituitary cells -- some very poorly known pituitary cells -- called folliculostellate cells (FSC). Probably many endocrinologists may not even be that familiar with these cells, because they are very poorly known.

I discovered that these cells were releasing some endothelial cell growth, which at the time was a mysterious factor. That was really intriguing at the time; I didn't know what to make of it, but I was very curious. I ended up following up on it.

I did a second postdoc in a different lab where I learned some protein biochemistry, and I tried to isolate this factor. It was at Genentech that we completed this work. Thanks to those wonderful facilities and state-of-the-art technology, we were able to sequence this molecule, which now is known as VEGF, and then we cloned it and we identified all of things that characterized this factor over several years.

Dr. Topol: If you go back a couple of decades, could you ever have envisioned that that curiosity would lead to what it did?

Dr. Ferrara: To be honest with you, it was a dream. It was a hope, but it would have been very, very difficult to imagine that. First, it was not clear at all that working on FSC, even though it was intellectually stimulating or interesting, could have such a broad application. Starting from a rather -- for lack of a better word -- obscure field and ending up with this implication would have been certainly hard to imagine.

From Discovery to Life-Saving Treatments

Dr. Topol: Now connect the dots. You make this discovery from these follicular rare or obscure cells, and then that eventually leads to the development of Avastin and Lucentis, treatments for cancer and macular degeneration. How do you go from that curiosity to changing the lives of so many people?

Dr. Ferrara: We found something that turned out to be very important, which is something, of course, you cannot predict. VEGF certainly was not the first angiogenic factor to be discovered. Actually, there was some seminal idea in the field that angiogenesis is important in embryonic development.

There was the study done in the 1940s by Michaelson[1] postulating the existence of a factor produced by the retina, which was called factor X. Even before that, there were some early studies postulating the existence of a tumor angiogenesis factor. So, in a way, one has to recognize that the biological context was already there.

People have tried many factors, but none of them seemed to be particularly important. For example, remember that the fibroblast growth factor (FGF) family of proteins has been extensively investigated, but FGF does not have a vascular phenotype. It was very fortunate that VEGF proved to be such an important molecule in angiogenesis.

Dr. Topol: Was it just serendipity, or what do you think led these successful drugs that are used in routine medical practice for different indications?

Dr. Ferrara: Well, I think it's a combination. First of all, when you find something, it will be luck, but I think I was a little bit persistent in development.

Dr. Topol: A little bit? You were chipping away at it for many years.

Dr. Ferrara: It took many years.

Dr. Topol: Were you frustrated along the way that you had this thing that you could see your way through as a therapeutic, but it wasn't getting legs, it didn't move fast enough?

Dr. Ferrara: Well, once again, the idea that it could be therapeutically relevant was not obvious from the very beginning. It's something that we built over the years. Initially, we did lots of fundamental research in biology. We studied the role of this molecule.

Dr. Topol: You covered the waterfront studying the biology and in vivo.

Dr. Ferrara: Yes, yes.

Dr. Topol: But what was it like when the very first patient was treated? What was it like when you got the word that this research was having an effect?

Dr. Ferrara: I think it was a really very, very, very long and frustrating path because, like all the cancer trials, there was initially some phase 1 success, and there were some very promising findings in phase 2, which was nice and not predicted. But actually, the first part of the phase 3 research in patients with relapsed breast cancer was a negative trial, so it was incredibly frustrating, and lots of people were ready to say the story was over.

Fortunately, about 6 months later, we got the results of this definitive phase 3 study in patients with colon cancer, and it showed a very significant survival benefit, which was to everybody's surprise -- I dare say astonishment -- given the previous negative trial. So that was great and it was certainly welcome, but I would have never taken anything like that for granted.

Dr. Topol: Sure, I can understand that. You obviously had a remarkable experience in a wet laboratory. What is it like for you to let go for the clinical trials? You really don't have that much input in clinical trials. You're not steering that. Is that a sense of losing control of where this arc is going to go?

Dr. Ferrara: I don't know if I would say that, because you cannot do everything. I'm sure there were people who were much better at doing clinical trials than myself. I think I was, at least, intellectually participating in that. We discussed it a lot. I was very fortunate, actually, at Genentech to have some great colleagues, even in the clinical department.

Dr. Topol: So you could provide input for them?

Dr. Ferrara: Oh, yes.

Dr. Topol: Good.

Dr. Ferrara: We discussed the data thoroughly, so I think that was very gratifying.

Dr. Topol: You're the exemplar of translational medicine. You walk the walk. You go all the way from at the bench to treating how many hundreds of thousands, even millions of patients. That's pretty extraordinary.

Dr. Ferrara: Thank you. I've been very, very, very fortunate.


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