DEPARTMENT OF PATHOLOGY

Napoleone Ferrara, M.D.

Napoleone Ferrara, M.D.

  • Distinguished Professor of Pathology
  • Distinguished Adjunct Professor of Ophthalmology
  • M.D. - University of Catania Medical School, Catania, Italy
  • Residency Training - University of Catania Medical School, Catania, Italy
  • Fellowship Training - University of California, San Francisco
  • Internship - The Oregon Health Sciences University
  • Postdoctoral Research - University of California, San Francisco

Research Interests

The main research theme of my lab is the regulation of angiogenesis (the formation of new blood vessels). In 1989 we reported the isolation and cDNA cloning of vascular endothelial growth factor (VEGF). We then demonstrated that VEGF is a key regulator of angiogenesis in a variety of physiological processes including embryonic development, reproductive functions and skeletal growth. In addition, we discovered that VEGF is a major mediator of tumor angiogenesis. These studies led to the development of a humanized anti-VEGF antibody, bevacizumab (Avastin®), which was initially approved by the FDA in 2004 for the treatment, in combination with 5-FU-based chemotherapy, of first-line metastatic colorectal cancer. Subsequently, bevacizumab was approved by the FDA for the treatment of additional malignancies, including non-squamous non-small cell lung carcinoma and renal cell carcinoma.

My lab's studies on the role of VEGF in intraocular neovascularization also led to the clinical development of an anti-VEGF antibody fragment, ranibizumab (Lucentis®), as a potential therapy for wet (neovascular) age-related macular degeneration (AMD), the leading cause of blindness for people over the age of 55. In 2006, ranibizumab was approved for the treatment of wet AMD after multiple Phase III trials demonstrating that administration of such agent results in substantial visual acuity gains. Since 2006, the FDA has expanded the use of ranibizumab to other intraocular disorders.

We are presently focusing on investigating mechanisms of tumor angiogenesis alternative to VEGF, in particular the role of the microenvironment and of factors produced by immune cells and fibroblasts in resistance to VEGF inhibitors.

Representative Publications

  1. Leung, DW, Cachianes, G, Kuang, W-J, Goeddel, DV, Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 246, 1306-1309, 1989.
  2. de Vries, C, Escobedo, JA, Ueno, H, Houck, K, Ferrara, N, Williams, LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 255, 989-991, 1992.
  3. Kim, KJ, Li, B, Winer, J, Armanini, M, Gillett, N, Phillips, HS, Ferrara, N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 362, 841-844, 1993.
  4. Aiello, LP, Avery, R, Arrigg, R, Keyt, B, Jampel, H, Shah, S, Pasquale, L, Thieme, H, Iwamoto, M, Park, JE, Nguyen, H, Aiello, LM, Ferrara, N, King, GL. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 331, 1480-1487, 1994.
  5. Ferrara, N, Carver-Moore, K, Chen, H, Dowd, M, Lu, L, O'Shea, S, Powell-Braxton, L, Hillan, KJ, Moore, MW. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 380, 439-442, 1996.
  6. Presta, LG, Chen, H, O’Connor, SJ, Chisholm, V, Meng, G, Krummen, L, Winkler, M, Ferrara, N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 57, 4593-4599, 1997.
  7. Ferrara, N, Chen, H, Davis-Smyth, T, Nguyen, N, Gerber, H, Peers, D, Chisholm, V, Hillan, KJ, Schwall, R. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nature Med. 3, 336-340, 1998.
  8. Gerber, HP, Vu, TH, Ryan, AM, Kowalski, J, Werb, Z, Ferrara, N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nature Med. 5, 623-628, 1999.
  9. LeCouter, J, Kowalski, J, J, Foster, Zhang, Z, Rangell, L, Keller, G-A, Hass, P, DeGuzman, LFrantz, G, Peale, F, Gurney, A, Hillan, KJ, Ferrara, N. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature. 412, 877-884, 2001.
  10. Gerber, HP, Malik, A, Solar, G, Sherman, D, Liang, XH, Meng, G, Hong, K, Marsters, JC, Ferrara, N. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 417, 954–958, 2002.
  11. LeCouter, J, Moritz, DR, Li, B, Phillips, GL, Liang, X-H, Gerber, HP, Hillan, KJ, Ferrara, N. Angiogenesis-independent endothelial protection of liver: Role of VEGFR-1. Science. 299, 890-893, 2003.
  12. Ferrara, N, Gerber, HP, LeCouter, J. The biology of VEGF and its receptors. Nature Med. 9, 669-676, 2003.
    Hurwitz, H, Fehrenbacher, L, Novotny, W, Cartwright, T, Hainsworth, H, Helm, W, Berlin, J, Baron, A, Griffing, S, Holmgren, E, Ferrara, N, Fyfe, G, Rogers, B, Ross, R, Kabbinavar, F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335-2342, 2004.
  13. Ferrara, N. Kerbel, RS. Angiogenesis as a therapeutic target. Nature. 438, 967-974, 2005.
    Shojaei, F, Wu, X, Baldwin, ME, Zhong, C, Malik, A, Shanz, S, Fuh, G, Gerber, HP, Ferrara, N. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnol. 25, 911-920, 2007.
  14. Shojaei, F, Wu, X, Zhong, C, Yu, L, Liang, XH, Yao, J, Blanchard, D Peale, F, Bais, C, Van Bruggen, N, Ho, C, Ross, J, Tan, M, Carano R, Meng, YG, Ferrara, N. Bv8 regulates myeloid cell-dependent tumour angiogenesis. Nature. 450, 825-831, 2007.
    Crawford, Y, Kasman, IM, Yu, L, Zhong, C, Wu, X, Modrusan, Z, Kaminker, J, Ferrara, N. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 15, 21-34, 2009.
  15. Shojaei, F, Wu, X, Qu, X, Tan, M, Meng, G, Ferrara, N. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF treatment in mouse models. Proc. Natl. Acad. Sci. USA. 106, 6742-6747, 2009.
  16. Bais, C, Wu, X, Yao, J, Crawford, Y, McCutcheon, K, Tan, C, Yang, S, Vernes, JM, Easthan-Anderson, J, Haughney, P, Kowanetz, M, Hagenbeck T, Kasman, I, Meng, G, Hongo, JA, Stephan, JP, Shibuya, M, Ferrara, N. PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell. 141, 166-177, 2010.
  17. Singh, M, Ferrara, N. Modeling and predicting clinical,efficacy for drugs targeting the tumor milieu. Nature Biotechnol. 30, 648-657, 2012.
  18. Zhuang, G, Wu, X, Jiang, Z, Kasman, I, Yao, J, Guo, Y, Oeh, J, Modrusan, Z, Bais, C, Sampath, D Ferrara, N. Tumor secreted miR-9 promote endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J. 31, 3513-3523, 2012.
  19. Phan, V, Wu, X, Cheng, J, Sheng, R, Chung, A, Zhuang, G, Tran, C, Song, Q, Kowanetz, M, Sambrone, A, Tan, M, Meng, YG, Jackson, EL, Peale, F,  Junttila, M, Ferrara, N. Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil recruitment. Proc. Natl. Acad. Sci. USA. 110, 6079-6084, 2013.
  20. Chung, AS, Wu, X, Zhuang, G, Ngu, H, Zhang, N, Kasman, I, Jiang, Z, Meng, G, Peale, F, Ouyang, W, Ferrara, N. IL-17 mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nature Med. 19, 1114-1123, 2013.
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Awards and Honors

  • Gairdner Foundation International Award 2014
  • Breakthrough Prize in Life Sciences 2013
  • The Economist Innovation Award (Bioscience) 2012
  • Dr. Paul Janssen Award for Biomedical Research 2011
  • ARVO/AFER, Special Recognition  2011
  • Lasker-DeBakey Clinical Medical Research Award 2010
  • Macula Society-Michaelson Symposium Award 2010
  • Pezcoller Foundation-AACR International Award 2009
  • Macula Society Arnall Patz Award 2008
  • Doctor honoris causa. University of Eastern Piedmont, Novara, Italy 2007
  • ASCO Science of Oncology Award 2007
  • Biotech Hall of Fame. Special Recognition for Scientific Achievement 2007
  • C. Chester Stock Award Lecture. Memorial Sloan-Kettering Cancer Center 2007
  • General Motors Cancer Research Award 2006
  • Passano Award 2006
  • Elected to the National Academy of Sciences 2006
  • AACR Bruce F. Cain Memorial Award 2005
  • Lefoulon-Delelande-Institut-de-France Prize 2005
  • American-Italian Cancer Foundation Prize 2004
  • Italian Association for Research and Therapy of Eye Disorders (AIRCMO) Prize 2004
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