Napoleone Ferrara Receives the 2010 Lasker~Debakey Clinical Award for Breakthroughs in Angiogenesis Research
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Napoleone Ferrara receives the 2010 Lasker~DeBakey Clinical Award for breakthroughs in angiogenesis research Ushma S. Neill J Clin Invest. 2010;120(10):3409-3412. https://doi.org/10.1172/JCI45092. News When Napoleone Ferrara was a medical student in Italy in the 1970s, he became interested in reproductive endocrinology. Although his training never specifically focused on angiogenesis, he is recognized today for shaping the field through the discovery of its core signaling molecule, VEGF, and for exploiting VEGF for the first successful clinical treatments of wet age-related macular degeneration (AMD) and cancer. On September 21, 2010, the Albert and Mary Lasker Foundation announced they will present Ferrara (Figure 1) with the 2010 Lasker~DeBakey Clinical Medical Research Award for his work on VEGF, which led to an effective therapy for neovascular AMD. Ferrara spoke with the JCI about his journey from discovery to treatment. Revving the endocrine engine Ferrara grew up in the shadow of the most active European volcano in Catania, Sicily. His father was a judge, and others in his family were in the legal profession, but his interest in the life sciences started even in high school: “To me,” Ferrara said, “it was much more interesting than the law.” He followed his passion to medical school, where he felt fortunate to land in the laboratory of Umberto Scapagnini. Ferrara noted that the University of Catania was much better known for its clinical focus than for its research, but “along came this dynamic young pharmacology professor who had trained for […] Find the latest version: https://jci.me/45092/pdf News Napoleone Ferrara receives the 2010 Lasker~DeBakey Clinical Award for breakthroughs in angiogenesis research When Napoleone Ferrara was a medi- knew best, and the endocrine cells that con- had the opportunity to go back to Italy, he cal student in Italy in the 1970s, he became trolled ovarian function were located in the said, “my heart wanted to stay in the United interested in reproductive endocrinology. pituitary gland; in Weiner’s lab, he began States and keep going with work I thought Although his training never specifically to study how they grew and functioned. was important.” The biotechnology com- focused on angiogenesis, he is recognized He isolated and cultured follicular cells, a pany Genentech in South San Francisco today for shaping the field through the dis- population of non–hormone-secreting cells provided just the opportunity he was look- covery of its core signaling molecule, VEGF, from the anterior pituitary of cows (1) that ing for: Genentech not only was known and for exploiting VEGF for the first suc- Ferrara called “very strange, and still after for ground-breaking science, but had also cessful clinical treatments of wet age-relat- decades . very obscure.” The follicular cultivated an atmosphere of academic dis- ed macular degeneration (AMD) and can- cells had cytoplasmic projections in inti- covery, encouraging employees to pursue cer. On September 21, 2010, the Albert and pet projects in their free time as long as the Mary Lasker Foundation announced they assigned work was done. Ferrara was hired will present Ferrara (Figure 1) with the 2010 to work on relaxin, an experimental treat- Lasker~DeBakey Clinical Medical Research ment to ease childbirth, but relaxin ended Award for his work on VEGF, which led to up a failure in clinical trials, and that proj- an effective therapy for neovascular AMD. ect was soon abandoned. But during his Ferrara spoke with the JCI about his jour- time working on relaxin, the angiogenic ney from discovery to treatment. seed planted in Weiner’s lab began to sprout: Ferrara noted, “We had some par- Revving the endocrine engine tially purified proteins with promising Ferrara grew up in the shadow of the most activity, but there was certainly a long way active European volcano in Catania, Sicily. to go.” He spent nights and weekends col- His father was a judge, and others in his lecting and processing supernatants from family were in the legal profession, but his cow pituitary cultures and exploring the interest in the life sciences started even in resultant proteins in the hopes of isolating high school: “To me,” Ferrara said, “it was the one that made endothelium proliferate. much more interesting than the law.” He In 1989, he finally isolated the angiogenic followed his passion to medical school, protein specific for vascular endothelial where he felt fortunate to land in the lab- cells, which had an amino acid sequence oratory of Umberto Scapagnini. Ferrara that matched that of no known sub- noted that the University of Catania was stance; he termed it vascular endothelial much better known for its clinical focus growth factor (2). Around the same time, than for its research, but “along came this an independent group uncovered the gene Figure 1 dynamic young pharmacology professor Napoleone Ferrara, winner of the 2010 Lasker~ (3) for vascular permeability factor (VPF), who had trained for years at University of DeBakey Clinical Award. a protein that Harold Dvorak had identi- California, San Francisco (UCSF). I’m sure fied in 1983 (4) on the basis of its ability he started my interest in research: he told to elicit blood vessel leakage. However, VPF such new and fascinating stories.” had not been fully purified, sequenced, or Scapagnini introduced Ferrara to Richard mate contact with the perivascular spaces, cloned, and little was known about this Weiner at UCSF. After finishing his medi- which suggested they might have a func- factor. Sequence comparison later showed cal training in Italy, Ferrara began a post- tion in regulating the pituitary vasculature. that the VPF and VEGF genes were identi- doctoral fellowship in Weiner’s laboratory, One day, Ferrara tried adding conditioned cal. Further testing determined that VEGF studying the dopaminergic regulation of media from cultures of follicular cells to was crucial for tumor angiogenesis, and prolactinomas. He remembered from his endothelial cells. The endothelial cells pro- we now know that of the more than 200 reproductive endocrinology training that liferated more rapidly, and this planted the kinds of human cancer, greater than half cyclical growth of blood vessels in the ova- seed in Ferrara’s head that the follicular cells produce VEGF. “This work started as ries is essential for fertility. In addition, the could be secreting an angiogenic agent. really basic research about angiogenesis literature that he studied revealed numer- in the pituitary,” Ferrara said, but he knew ous examples of an overgrown vasculature Discovering VEGF about Judah Folkman’s original hypothesis lying at the heart of the disease pathology. In 1988, Ferrara decided to move on from about choking tumors by shutting off their But Ferrara pursued the system that he his postdoctoral fellowship. Although he blood supply (5) — “we knew this could go The Journal of Clinical Investigation http://www.jci.org Volume 120 Number 10 October 2010 3409 news beyond the basic research and solve a mys- Nature (11, 12) showing an essential role failed to meet its primary efficacy endpoint tery which could go much broader, like to of VEGF in embryonic vasculogenesis in of survival in a phase III breast cancer trial. tumors or reproduction.” the mouse: deletion of a single VEGF allele Ferrara was disappointed, but still had some Ferrara credits the culture at Genentech resulted in embryonic lethality between hope. “It did not increase the survival, but for giving him the time and resources to days 11 and 12. Ferrara said, “These genetic there was some evidence that the treatment dedicate to the discovery of VEGF: “At experiments truly validated the ideas about shrank some tumors in the trial. Also, these the very beginning, this was a purely dis- the central role for VEGF in angiogenesis.” patients were in third-line therapy,” meaning cretionary project. No one really thought While Ferrara explored the basic biology they had already been treated by two other this would be therapeutic, but Genentech of VEGF and its mechanisms of action, methods that had failed. “This is a very high always had their liberal policy to allow sci- given how well the murine antibody bar for a trial. The patients were in a much entists to explore. There are so many prom- worked, Genentech was eager to develop a more advanced stage and very sick.” ising molecules that don’t go on to have version that could be used to treat humans. Happily, preliminary results from a any relevance to what you’re looking for.” Ferrara worked closely with Leonard Pres- phase II renal cell carcinoma trial showed ta, at that time Genentech’s authority on that Avastin did meet its primary efficacy Harnessing VEGF for therapy antibody humanization, to develop what endpoint (16). That trial was the first step Ultimately, Ferrara knew he was employed ultimately became bevacizumab (Avastin). toward FDA drug approval. Trials were by a company, and that he needed to turn Like its murine counterpart, bevacizumab also already ongoing in 925 patients diag- his attention to exploiting VEGF as a thera- binds and neutralizes all human VEGF-A nosed with previously untreated meta- peutic target. He and other Genentech scien- isoforms and bioactive proteolytic frag- static colon cancer. Comparison of the tists initially developed a murine anti-VEGF ments, but does not interact with mouse or median survival time of patients treated monoclonal antibody that exerted a potent rat VEGF (13). Ferrara explained that the with irinotecan/5-fluorouracil/leucovorin inhibitory effect on the growth of three antibodies have been “engineered in such (IFL) chemotherapy in combination with tumor cell lines injected subcutaneously in a way that approximately 7% of the murine Avastin and patients treated with IFL and nude mice (6).