Swedish scientists at the Karolinska Institutet and the biotech company AngioGenetics have shown that a protein called Delta-like 4 (Dll-4) controls how many new blood vessels 'shoot' out from existing ones, a process called angiogenesis. All tissue needs a good blood supply to survive and grow. In the case of cancer, a tumour cannot grow larger than approximately 2mm without forming new blood vessels. Inhibiting this process has proved effective in treating multiple types of cancer and also age-dependant macula degeneration, the leading cause of blindness in the US.
So far, most drugs that aim to prevent angiogenesis target vascular endothelial growth factor (VEGF). This protein controls several aspects of angiogenesis through signalling via receptors on the surface of the endothelial cells that line blood vessels. For example, new blood vessels grow along VEGF gradients and so it controls the direction of vessel shoots.
The discovery of a new protein that helps control angiogenesis provides pharma companies with a new target for drugs and researchers believe they could be just as important as those that target VEGF. In the US alone, there are over 350 clinical trials of drugs that in some way modulate VEGF, according to clinicaltrials.gov.
"We can now develop ways of boosting the effect of existing anti-angiogenic therapies, and maybe we can even start to treat tumour types that do not currently respond to anti-angiogenic drugs," said Mats Hellstrom, a scientist involved in the research.
When new blood vessels form, the shoots lengthen, branch off and contact other blood vessels as they form communicating networks of channels.
The researchers showed that inhibiting Dll-4 increased the number of new blood vessel shoots whereas activating Dll-4 using a soluble peptide increased the signalling between blood vessels and resulted in fewer shoot tips and vessel branches.
Together, this suggests that Dll-4 restricts tip-cell formation in response to VEGF and is therefore critical to attaining the correct density of vessels. Too great a blood supply can be just as damaging to tissue as too little.
Dll-4 can be restricted using gamma-secretase inhibitors. These compounds have been developed as a treatment for Alzheimer's disease because gamma-secretase is linked to the formation of amyloid plaques, which cause the devastating symptoms of the disease.
Alzheimer's disease has also linked to decreased blood flow in the brain, both in the past and in more recent research.
VEGF plays an important role in several medical pathways that are being investigated by pharmaceutical companies. The production of VEGF is controlled through the body's response to low oxygen levels (hypoxia). As oxygen levels fall below a certain level, a protein called hypoxia inducible factor (HIF) is produced in increasing levels. HIF binds to DNA and switches on several genes that promote survival, including the gene that produces VEGF.
Enzon Pharmaceuticals and Santaris recently announced the start of a Phase I trial of SPC2968, their drug that aims to inhibit the production of HIF.
Some of the genes associated with VEGF production are RAS, p53, C-Src and BCR-ABL. The production of VEGF is also associated with the levels of certain proteins inside the cell. For example, over production of human epidermal receptor (HER)-2 is linked to VEGF levels in colon, pancreatic, gastric, breast, renal cell, and non-small cell lung cancers.
EyeTech Pharmaceuticals, in conjunction with Pfizer, markets the anti-VEGF drug Macugen (pegaptanib sodium injection) as a treatment for all types of wet macular degeneration.
Genentech, in conjunction with Roche, developed the first anti-VEGF drug. Avastin (bevacizumab) is a recombinant humanized antibody currently approved for use in colon and rectum cancer and is in late stage trials for, breast, kidney, non-small cell lung, prostate and ovarian cancers. When Genentech recently announced Avastin sales figures of $1.7bn for 2006, an increase of 54 per cent over the previous year.
