1787: British surgeon Dr. John Hunter first uses the term "angiogenesis" (new blood vessel growth) to describe blood vessels growing in the reindeer antler.

1935: Boston pathologist Dr. Arthur Tremain Hertig describes angiogenesis in the placenta of pregnant monkeys.

1971: Surgeon Judah Folkman hypothesizes that tumor growth is dependent upon angiogenesis. His theory, published in the New England Journal of Medicine, is initially regarded as heresy by leading physicians and scientists.

1975: The first angiogenesis inhibitor is discovered in cartilage by Dr. Henry Brem and Dr. Judah Folkman.

1984: The first angiogenic factor (basic fibroblast growth factor, bFGF) is purified by Yuen Shing and Michael Klagsbrun at Harvard Medical School.

1989: One of the most important angiogenic factors, vascular endothelial growth factor (VEGF), is discovered Dr. Napoleone Ferrara. It turns out to be identical to a molecule called Vascular Permeability Factor (VPF) discovered in 1983 by Dr. Harold Dvorak.

1989: The first successful treatment of an angiogenesis-dependent benign tumor (pulmonary hemangioma) using interferon alfa2a is reported by Dr. Carl White, a pediatric radiologist in Denver.

1992: The first clinical trial of an antiangiogenic drug (TNP-470) begins in cancer patients.

1994: The Angiogenesis Foundation is founded to improve global efforts by facilitating the development and application of angiogenesis-based medicines.

1997: The first angiogenesis-stimulating drug (becaplermin, Regranex) is FDA-approved for treatment of diabetic foot ulcers.

1997: Dr. Michael O'Reilly publishes research finding in the journal Nature showing complete regression of cancerous tumors following repeated cycles of antiangiogenic therapy using angiostatin and endostatin.

1998: The first angiogenesis-stimulating laser is FDA-approved for the treatment of severe, end-stage coronary disease.

1999: The first vascular targeting therapy is FDA-approved for treatment of age-related macular degeneration.

1999: Massive wave of antiangiogenic drugs enter clinical trials: 46 antiangiogenic drugs for cancer patients; 5 drugs for macular degeneration; 1 drug for diabetic retinopathy; 4 drugs for psoriasis.

1999: Massive wave of angiogenesis-stimulating drugs enter clinical trials: 5 drugs for coronary artery disease; 5 drugs for peripheral vascular disease; 1 drug for stroke; 10 drugs for wound healing.

1999: Laboratory research led by Dr. Robert Kerbel and Dr. Judah Folkman shows that some traditional cytotoxic chemotherapies may inhibit tumor angiogenesis when given at low-doses.

1999: Dr. Richard Klausner, Director of the U.S. National Cancer Institute, designates the development of antiangiogenic therapies for cancer as a national priority. 2003 - The monoclonal antibody drug Avastin (Bevacizumab) becomes the first antiangiogenic drug to demonstrate in large-scale clinical trials that inhibiting tumor blood vessel growth can prolong survival in cancer patients.

2004: A pivotal phase 3 trial published in the New England Journal of Medicine shows that the addition of bevacizumab (Avastin), an anti-VEGF monoclonal antibody, to chemotherapy significantly improves survival in patients with metastatic colorectal cancer.

2004: Bevacizumab is FDA approved for the treatment of advanced colorectal cancer. At the time of bevacizumab’s approval, FDA Commissioner Mark McClellan declares antiangiogenic therapy “the fourth modality for cancer treatment.”

2004: Pegaptanib (Macugen), an anti-VEGF aptamer, becomes the first anti-VEGF drug to be FDA approved for the treatment of age-related macular degeneration.

2004: Erlotinib (Tarceva), a small molecule inhibitor of EGFR tyrosine receptor kinase, receives FDA approval for treatment of non-small cell lung cancer (NSCLC).

2005: Endostatin (Endostar), an agent that inhibits metastasis and angiogenesis by downregulating multiple proangiogenic growth factors, is approved in China for the treatment of advanced lung cancer.

2005: Sorafenib (Nexavar), a multi-tyrosine kinase inhibitor, demonstrates significantly longer progression-free survival vs. placebo in patients with advanced renal cancer in a randomized phase 3 trial.

2005: Sorafenib is FDA approved as second-line therapy for advanced renal cancer.

2005: Lenalidomide (Revlimid), and agent with both immumomodulatory and antiangiogenic properties, is FDA approved for treatment of myelodysplastic syndrome.

2006: Sunitinib (Sutent), a multi-tyrosine kinase inhibitor, receives FDA approval as first-line therapy for advanced renal cancer and gastrointestinal stromal tumor (GIST).

2006: Ranibizumab (Lucentis), a fragment of the bevacizumab molecule, is FDA approved for the treatment age-related macular degeneration.

2006: Bevacizumab in combination with paclitaxel and carboplatin is shown to significantly improve progression-free survival, overall survival, and response rates in treatment-naïve patients with advanced NSCLC. This is the first time an antiangiogenic agent plus chemotherapy has been shown to prolong survival in NSCLC patients.

2007: Results from a randomized phase 3 trial published in the New England Journal of Medicine show a significant survival benefit for sorafenib vs. placebo in patients with advanced renal cancer who fail first-line therapy.

2007: Temsirolimus (Torisel), an inhibitor of mTOR, is approved for the treatment of advanced renal cancer after a pivotal phase 3 trial published in the New England Journal of Medicine shows significantly improved progression-free survival in previously untreated mRCC patients with poor prognosis.

2007: Results from a randomized phase 3 trial published in the New England Journal of Medicine show that sunitinib doubles progression-free survival in previously untreated patients with metastatic renal cancer.

2007: Results announced at ASCO 2007 from a randomized phase 3 study show that sorafenib extends overall survival by 44% vs. placebo in patients with advanced liver cancer. Based on these findings, in November the FDA approves sorafenib to treat unresectable advanced hepatocellular carcinoma. Sorafenib is the first systemic agent to show efficacy for advanced liver cancer.

2008: Angiogenesis pioneer Dr. Judah Folkman passes away suddenly on January 14 while traveling to a conference. At the time of Dr. Folkman's death, an estimated 1.2 million patients had been treated with antiangiogenic therapy, a concept he first conceived of almost 4 decades prior. Dr. Folkman is widely recognized as one of the most important figures in modern medicine.

2008: In February, bevacizumab (Avastin) becomes the first antiangiogenic agent approved to treat breast cancer. The approval is based on phase 3 trial results in which BV/paclitaxel doubled median progression free survival versus paclitaxel alone (PFS: 11.8 mo. vs. 5.9 mo., P<0.0001) in women with locally recurrent or metastatic breast cancer.

READ MORE

Last updated June 23, 2009

References:
Ingber D, Fujita T, Kishimoto S, et al. Synthetic analogs of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 1990;348:555-557.

Folkman J, Klagsbrun M. Angiogenic factors. Science 1987;235:442-447

Li W. Tumor angiogenesis: molecular pathology, therapeutic targeting and imaging. Acad Radiol 2000;7:800-811.

Li WW, Hutnik M, Li VW, Angiogenesis-Based Medicine: Principles and Practices for Disease and Intervention. Angiogenesis: Basic Science and clinical applications (M.E. Maragoudakis and E. Papadimitrion, Editiors) in press.

Smiell JM, Wieman TJ, Steed DL, et al. Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Repair Regen. 1999;7:335-346.

White CW, Sondheimer HM, Crouch EC, et al. Treatment of pulmonary hemangiomatosis with recombinant interferon alpha-2a. N Engl J Med 1992;326:1456-1463