Genentech is a leader in research and development in angiogenesis, the process of forming new blood vessels. While angiogenesis normally occurs during certain stages of human development, the adult body produces new blood vessels infrequently — for example, once a month in women during menstruation, and as a part of wound healing in both men and women. In the context of cancer, tumor angiogenesis is the creation of a network of blood vessels that supplies tumors with essential nutrients and oxygen, and removes waste products.1
In 1989, Napoleone Ferrara, M.D., and a team of scientists at Genentech first isolated human vascular endothelial growth factor (VEGF), a protein now believed to be one of the most potent sources of angiogenesis.2, 3 The need for oxygen and nutrients triggers tumor cells to produce and release the VEGF protein, which leads to the formation of new blood vessels to feed the tumor. In addition to supporting tumor growth, these new vessels provide a "highway" along which tumor cells can travel through the bloodstream to other parts of the body. This may lead to the formation of new tumors and spread of cancer (metastasis). Sustained angiogenesis is a hallmark of most, if not all cancers.4 Without angiogenesis, a tumor would not likely grow beyond a few millimeters, the size of an average pencil eraser.3
Anti-Angiogenesis As researchers gained a greater understanding of VEGF and its role in angiogenesis, they turned their focus to creating therapies that could interfere with angiogenesis by targeting the VEGF protein, one of the most potent and predominant regulators of angiogenesis.
Therapies that inhibit VEGF may have multiple effects on angiogenesis, tumor growth and delivery of other types of therapy.5,6 These effects may include:
- Reducing the tumor's blood supply by potentially causing existing small blood vessels in the tumor to die.
- Preventing the development of new blood vessels in the tumor.
- Facilitating the delivery of chemotherapy to the tumor cells by potentially making mature tumor vessels, which tend to be leaky, behave more like normal vessels.
By inhibiting the VEGF protein, the blood supply to a tumor may be gradually reduced.
Avastin: The First Anti-Angiogenesis Treatment For Cancer In 1993, Dr. Ferrara and his team at Genentech produced a monoclonal antibody that specifically binds to the VEGF protein, preventing it from promoting new blood vessel growth.7 In 2004, after seven years of human clinical trials, the U.S. Food and Drug Administration (FDA) approved the antibody, known as Avastin® (bevacizumab), in combination with intravenous 5-fluorouracil (FU)-based chemotherapy for the first-line treatment of patients with metastatic colorectal cancer. Avastin is the first approved anti-angiogenesis treatment for cancer.
Avastin was initially approved based on the results of a Phase III study of the drug plus chemotherapy in previously untreated metastatic colorectal cancer patients. This study provided the first Phase III clinical validation of the long-standing hypothesis that targeting a tumor's blood supply via angiogenesis could be used as a cancer therapy.
In June 2006, the FDA approved Avastin in combination with intravenous 5-FU-based chemotherapy for the second-line treatment of patients with metastatic colorectal cancer. In October 2006, the FDA approved Avastin in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC).
Avastin Safety The most serious adverse events associated with Avastin across all trials were GI perforation, wound healing complication, hemorrhage, non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome, neutropenia and infection, nephrotic syndrome, and congestive heart failure. The most common grade 3-5 (non-hematologic) and 4-5 (hematologic) events that may have occurred in Avastin indications (first-line NSCLC, first- and second-line MCRC) included neutropenia, fatigue, hypertension, infection, hemorrhage, asthenia, abdominal pain, pain, deep vein thrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, nausea, vomiting, dehydration, ileus, neuropathy-sensory, neurologic-other, and headache.
For full prescribing information, including Boxed WARNINGS for Avastin and information about angiogenesis, visit www.gene.com. For more information on Avastin, visit www.avastin.com.
Avastin Development Program Based on data showing that the VEGF protein may play a broad role in a range of cancers, a global development program for Avastin currently includes more than 450 clinical trials in more than 30 different tumor types, including early-stage cancers. It is also being studied in combination with other targeted therapy agents in the absence of chemotherapy.
References
1 Rosen LS. Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control. 2002;9:36-44.
2 Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted antiogenic mitogen. Science. 1989;246:1306-1309.
3 Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D, Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem. 2006;13:1845-1857
4 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
5 Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer . 2002;2:727-739.
6 Jain RK. Normalizing tumor vasculature with antiangiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987-989.
7 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. 1993;362:841-844.