Anti-Angiogenic Drugs to Treat Human Disease: an Interview with Napoleone Ferrara

Disease Models & Mechanisms 2, 324-325 (2009) doi:10.1242/dmm.002972 A MODEL FOR LIFE Published by The Company of Biologists 2009

Anti-angiogenic drugs to treat human disease: an interview with Napoleone Ferrara

Napoleone Ferrara identified vascular endothelial growth factor (VEGF) as a major regulator of blood vessel development. The antibodies that he and his colleagues created to block VEGF action also block cancer growth. Here, he discusses the work that led to the development of the anti-cancer drug Avastin (bevacizumab), and discusses the role of basic science in clinical medicine.

he formation of new blood But none of the molecules that were ini- vessels, or angiogenesis, is neces- tially characterized as potential angiogenic sary for the development of most factors seemed to be important as endoge- multicellular organisms. The new nous regulators. For example, basic fibrob- vessels allow for the perfusion of last growth factor (bFGF) was one of the Torgans and tissues, including those involved first factors to be purified and characterized in normal embryonic development, repro- as an angiogenic factor. It was extremely ductive function and skeletal growth. potent in several in vitro and in vivo

DMM However, promoting blood vessel develop- systems, but then when researchers tried to ment also allows tumors to obtain neces- block bFGF function with antibodies, it had sary nutrients and survival factors and to little effect on tumor growth. Even the eliminate catabolic products. In 2004, Dr knockout of the gene for bFGF did not Ferrara’s work at Genentech led to the first result in any obvious defect in vascular de- Food and Drug Administration (FDA) ap- velopment, so clearly something was genic factor that regulated blood vessel for- proval of the anti-VEGF antibody, under the missing. One of the lessons from these mation was isolable from that supernatant. drug name Avastin, as part of an anti- studies was the fact that although a mole- After several years, I was finally able to cancer combination therapy to block an- cule may have activity as a pharmacological purify VEGF, and sequence and clone it. giogenesis in colorectal cancer. Since then, agent, it does not prove that the molecule is That is how the discovery of VEGF hap- the applications for blocking VEGF func- important physiologically. pened. tion have increased along with our under- I was probably fortunate that my work standing of normal and pathological angio- was in a different field from cancer, as this When you were first looking at angiogenesis. gave me a fresh perspective. I worked on the genic regulation, you were in the field of pituitary gland when I was a post-doc at the reproductive biology. Did you immedi- What events led to your identification of University of California, San Francisco ately recognize its importance in cancer? Disease Models & Mechanisms VEGF and its crucial role in angiogene- (UCSF). My interest was a group of cells in At that time there was reason to believe that sis? the pituitary that do not produce hor- an angiogenic factor might be important in The regulation of angiogenesis has been a mones, termed ‘follicu- several situations. This long-standing issue, which was very exciting lar cells’. What was in- was supported by evi- to a number of investigators, not only tumor triguing to me about You can effectively dence that growth biologists but also ophthalmologists and, of these cells was that translate only good basic factors were important, course, to developmental biologists. When there was some intimate research and that is really not only in a specific I started working in this field, in the early to connection between tissue or organ, but that mid 1980s, clearly a major question was them and the vascular the foundation of any their actions had much ‘what are the important angiogenic factors?’ spaces. It looked as advance in medicine broader implications. So, The idea of the existence of an angiogenic though the cells could it was conceivable that a factor (or factors) is quite old. It was origi- potentially regulate the growth and main- molecule that regulates physiological an- nally proposed in the late 1930s and people tenance of the vessels. giogenesis could be also potentially impor- have been trying to purify such a factor for I decided to test whether the supernatant tant in pathological angiogenesis. a long time. from these cells had any mitogenic effect on endothelial cells. To my delight, I found a Once the physiological significance of strong mitogenic effect. Of course, this was VEGF was realized, how did you use the only the very, very first step and there was information to develop a relevant drug? Napoleone Ferrara is a Genentech Fellow in the Department of Molecular Oncology at Genentech a long way to go ahead, but I ended up pur- It took several steps. We realized the impor- (e-mail: [email protected]) suing this idea (or dream) that the mito- tance of VEGF as a mediator of pathological

324 dmm.biologists.org Napoleone Ferrara A MODEL FOR LIFE

angiogenesis even before we fully appreci- esis is involved in a lot of normal and unsuccessful. I believe that if you can ated its role as a physiological mediator. At pathological processes. Do you picture combine data from multiple models, you the time, VEGF was an intriguing new mol- some of these drugs having other pur- become more likely to identify a common ecule. It looked exciting, but there were poses in addition to treating cancer pa- theme and derive some information that already a range of angiogenic factors that tients? should be applicable to humans, keeping in were known. It was possible that VEGF was There are diseases in which anti-angiogenic mind that it is virtually impossible to fully just one of many regulators of angiogenesis, therapy with VEGF inhibitors has been recreate human disease in animals. such that blocking its action could have a quite successful. In 2006, the FDA approved very limited impact. So, we put a consider- Lucentis (ranibizumab), an anti-VEGF an- What is it like to work at Genentech? able amount of effort in to understanding the tibody derived from the same murine anti- Traditionally, Genentech has put lots of em- role of VEGF. We knocked out the VEGF body as Avastin, as a therapy for neovascu- phasis on basic research. Really, it’s the gene and got a very surprising result. Even if lar age-related macular degeneration, the closest thing to academia you can find in in- we knocked out only one of the two VEGF leading case of blindness in the working dustry. alleles in mice, they died because of insuffi- population. In such conditions, blocking I must say that my job has a number of cient vascular development. This was very VEGF has a quite dramatic effect and similarities to academia because I do mostly compelling evidence that VEGF was impor- almost completely inhibits the growth of research. In addition, the opportunity to in- tant. We published this in 1996, but even vessels in choroidal neovascular mem- terface with a variety of groups such as de- prior to reporting these findings we devel- branes. Patients can even gain some visual velopment, safety evaluation, clinical, etc., oped antibodies to human VEGF, and we acuity when they are treated with anti- makes it a particularly interesting and stim- were able to show that these antibodies could VEGF. Other possible indications are dia- ulating environment. block tumor growth by blocking the vascu- betic retinopathy and retinal vein occlusion. larization of tumor cell lines implanted in I believe that the application of anti-VEGF What do you do when you have identified

DMM mice. therapy to eye diseases is particularly excit- a molecule that you think clearly has ing. therapeutic potential? What is the next How important is your clinical experience step? in your research and drug discovery? Do you have a favorite model organism We try to understand what the molecule At this point, I hardly consider myself a clin- for understanding tumor biology? does. It is important to determine what ician. I have a medical background and I did We work on numerous models, utilizing happens if you inactivate it or if you over- some clinical training. This training gave me mostly mouse models. We work on express it. We then develop antagonists and a biological background that allowed me to xenografts, as well as with genetic models. other tools that allow us to test our hy- have a greater appreciation of physiology and There isn’t a perfect model – each model is potheses in in vitro and in vivo systems. pathology, but I cannot say that right now I a model of itself and it’s probably in the can consider myself a practicing clinician. combination and in assessing multiple Do you have any advice for young scien- models that you can hope to find something tists who are interested in living at this Once you created a functional antibody in common. interface between research and bringing with clinical application, did your work Although we have rat models and nude about new therapeutics? proceed in conjunction with a drug rat models, frankly, I don’t believe they rep- Each situation is very different and it is dif- company? resent any step beyond mice and they are ficult to generalize. I would say that ‘trans- Disease Models & Mechanisms Well, that was a really nice aspect. I was in less well characterized. The mouse is still lational research’ is not a very well defined an environment where I was allowed not king in the area of cancer modeling. There area and to many people it is not very clear only to do research but, at the same time, are so many genetically modified mice what it is. I would suggest that translational there was a strong interest in developing available that can allow you to test many hy- research is only as good as the basic re- therapeutics. potheses. search that supports it. You can effectively translate only good basic research and that Does your medical background influence Are there specific things that you must is really the foundation of any advance in your approach to basic science? consider when using information gained medicine. I truly believe it does because my research from a model organism and applying it to DMM greatly appreciates Napoleone is always oriented towards some medically humans? Ferrara’s time and willingness to share his significant question. Even in my early work, You have to be always mindful that there is personal story. We are grateful for the op- I tried to identify angiogenic factors. This not a single model that can recapitulate the portunity to present his story here as A was an attempt to address questions about complexity of a human. There are so many Model for Life. basic science with clinical implications. variables and from these you have to choose Napoleone Ferrara was interviewed by the ones that you wish to test. So far, most Kristin H. Kain, Associate Reviews Editor for The anti-VEGF antibody (Avastin) is now of the attempts to make therapeutic pre- DMM. This piece has been edited and con- a proven anti-cancer drug but angiogen- dictions based on a single model have been densed with approval from the interviewee.

Disease Models & Mechanisms 325