The idea of starving tumours by interrupting their blood supply has, despite initial drawbacks, generated the production of blockbuster drugs and is now a major R&D focus for biotechnology and pharmaceutical companies. But the biological effects are more complicated than originally expected.
The growth of solid tumours depends on the generation of new blood vessels from pre-existing ones in order to guarantee the supply of nutrients to the tumours. This process is referred to as angiogenesis. About 38 years ago, Judah Folkman from the Harvard Medical School published a groundbreaking paper in the New England Journal of Medicine (285, 1182-1186, 1971) in which he postulated that the inhibition of angiogenesis would lead to the destruction of the tumour.
This concept of treating cancers was initially pursued by many researchers, but lost its attraction after two of the angiogenesis inhibitors, angiostatin and endostatin, discovered in Folkman's laboratory, were unable in clinical studies to fulfil the expectations of the researchers. The development of the antibody bevacizumab, another angiogenesis inhibitor, by the Californian biotech company Genentech finally led to the breakthrough in this field.
Bevacizumab is a humanised monoclonal antibody that inhibits angiogenesis by binding to the vascular endothelial growth factor (VEGF), a growth factor promoting the generation of new blood vessels. In 2004, the antibody was approved by the American FDA for the treatment of metastasising colorectal carcinoma in combination with chemotherapy. Further approvals followed for combination therapies for the treatment of advanced and metastasising tumours, including non-small cell bronchial carcinoma (lung cancer), renal cell carcinoma and breast cancer. In 2008, bevacizumab, which is marketed by the Swiss pharmaceutical company Roche (which acquired Genentech in 2009) under the brand name Avastin®, achieved a worldwide sales revenue of US$ 4.8 billion and is thus one of the most important biopharmaceutical blockbuster drugs. Numerous clinical Phase III trials are currently underway to test Avastin – alone or in combination with chemotherapy – for its efficiency against other types of tumours. On March 31 2009, the FDA recommended its use for the treatment of glioblastoma, which is the most aggressive brain tumour known, and which often leads to the death of patients within six months of diagnosis. In May 2009, the FDA will decide whether it will grant Avastin rapid approval for the treatment of glioblastoma.
In the last few years, two additional angiogenesis inhibitors targeting the VEGF growth factor have entered the market. One of these inhibitors is sunitinib, used for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumours (GIST, a relatively rare gastrointestinal sarcoma). It is marketed as Sutent® by Pfizer. The second inhibitor is sorafenib, which was developed by the biotech company Onyx in San Francisco and which was launched by Bayer as Nexavar® for the treatment of kidney and liver cancer. In contrast to the therapeutic antibody Avastin, these two drugs are low molecular substances that are directed against kinases that regulate the VEGF system. The two substances are currently undergoing clinical phase III testing for the treatment of other cancers.
Sutent (sunitinib) blocks the VEGFR2 receptor on the surface of endothelial cells that line the interior surface of blood vessels. This receptor works as a switch: When the growth factor VEGF, which is highly expressed by tumour cells, is bound to this receptor, a signalling chain is triggered in the endothelial cells which induces new blood vessels to grow towards the tumour. Blocking of this switch prevents blood vessels from growing around and into the tumour tissue. In addition to blocking angiogenesis, Sutent® also inhibits additional enzymes that are involved in the development of tumours. The discovery of the drug and clarification of the multi-specific mechanism of action is based on discoveries of Axel Ullrich and his team at the Max Planck Institute of Biochemistry in the 1980s in Munich. Medical and pharmaceutical development as well as clinical testing of the drug was carried out by Sugen, a company founded in 1991 by Ullrich and his American colleague Joseph Schlessinger (the S in Sugen stands for Schlessinger, the U for Ullrich), also involving New York University and the Max Planck Society. In order to acquire capital for clinical testing, Sugen was sold to the Swedish company Pharmacia in 1999 for US$650 million. In 2003, Pharmacia was acquired by Pfizer for US$60 billion. Pfizer quickly advanced the development of the drug and Sutent® was approved by the FDA and EMEA in 2006. Thanks to the money made from the sale of the Sugen shares, from patents and through licensing, Sutent is the biggest technology transfer success of the Max Planck Society (Max Planck Innovation, formerly Garching Innovation) in the biotechnology and pharmaceutical sector. The example of Sutent well illustrates the extremely long road taken by drugs from the laboratory bench to marketing authorisation, a road that is both full of obstacles and extremely costly. It is worth noting that Sutent benefited from outstanding conditions for its development: With Axel Ullrich, the new company had one of the most renowned international scientists with an excellent industrial background at its dispostion; he is one of the few German “serial founders”, i.e. founder or cofounder of the biotech companies Sugen, Axxima, U3 and Kinaxo. After his doctorate, Ullrich went to the States to work in Ekkehard Bautz’s molecular biology laboratory at the University of California, San Francisco (UCSF) and was one of the first people to join Genentech. He cloned the human insulin gene, which was the basis for the first ever drug (i.e., the human insulin drug Humulin) produced using genetically engineered bacteria for the treatment of diabetes. Ullrich also made considerable contributions to the development of Herceptin® (trastuzumab), a therapeutic antibody targeting the receptor of the epidermal growth factor, which is used for the treatment of certain breast cancers.
Besides the three FDA/EMEA-approved angiogenesis inhibitors Avastin, Sutent and Nexavar, the big pharmaceutical and biotechnology companies have about eight additional drugs that target the VEGF signalling pathway in clinical phase III trials. These include BIBF1120, developed by Boehringer Ingelheim for the treatment of lung cancer, a drug that simultaneously acts on three targets: VEGFR, the FGF receptor (fibroblast growth factor) and PDGF (platelet growth factor). It is hoped that this will lead to reliable and permanent clinical benefits in the treatment of cancer. In the meantime it has become obvious that the treatment of cancer with anti-angiogenetic drugs is far more complicated than Folkman envisaged. A recent article in the journal Nature (9 April 2009, Cutting off cancer's supply lines, Nature 458, 686-687) discusses a range of complications associated with anti-angiogenetic drugs. In animal experiments it was discovered that the effect of anti-angiogenetic drugs depended on the dosage and the time the drug was applied; in some cases, the drug even stimulated tumour growth and metastasis.
This does not mean that the angiogenesis concept is unsuitable for the treatment of tumours; huge success has been achieved with the aforementioned drugs. But it is obvious that a lot of research is required to improve cancer therapy. "Nature" quotes Donald McDonald from the UCSF, an expert in this area: "Avastin is chapter one of angiogenesis inhibition, and we're going to move on to chapter two and chapter three. And with each chapter there will be more clinical benefit as we gain a better understanding of the underlying biology."