One promising avenue of cancer research is the study of a group of compounds called angiogenesis inhibitors. These are drugs that block the development of new blood vessels, a process known as angiogenesis. Solid tumors cannot grow beyond the size of a pinhead (1 to 2 cubic millimeters) without inducing the formation of new blood vessels to supply the nutritional and other needs of the tumor. By blocking the development of new blood vessels, researchers are hoping to cut off the tumor's supply of oxygen and nutrients, and therefore its continued growth and spread to other parts of the body.
About 20 angiogenesis inhibitors are currently being tested in human trials. Most are in early phase I or II clinical (human) studies. Some are in or entering phase III testing. In Phase I/II trials, a limited number of people are given the drug to determine its safety, dosage, side effects, and preliminary activity. In phase III trials, hundreds of people around the country are involved in studies to determine how effective the drug is. Although the design of phase III studies may vary, in general all patients receive standard therapy: half of all patients receive standard therapy plus the new drug and the other half receive standard therapy and a placebo.
- See table of angiogenesis inhibitors in clinical trials
In normal tissue, new blood vessels are formed during tissue growth and repair, during the normal female reproductive cycle, and during the development of the fetus during pregnancy. In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth.
Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel becomes activated, makes matrix metalloproteinase enzymes (MMPs) that break down the extracellular matrix (the surrounding tissue), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible.
Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New vessel growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it.
About 15 proteins are known to activate endothelial cell growth and movement, including vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (aFGF and bFGF), angiogenin, epidermal growth factor (EGF), scatter factor (SF), placental growth factor (PlGF), interleukin-8, and tumor necrosis factor alpha (TNF-alpha), to name a few. Some of the known naturally occurring inhibitors of angiogenesis include angiostatin, endostatin, interferons, platelet factor 4 (PF4), thrombospondin, transforming growth factor beta, 16Kd fragment of prolactin, and tissue inhibitor of metalloproteinase-1, -2, and -3 (TIMP-1, TIMP-2 and TIMP-3).
At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and bFGF, are expressed by many tumors and seem to be among the most important angiogiogenic activators in sustaining tumor growth.
Angiogenesis is also related to metastasis, which is the spread of a tumor to different parts of the body. It is generally true that tumors with higher densities of blood vessels are more likely to spread and have poorer clinical outcomes. Also, the shedding of large numbers of tumor cells from the primary tumor may not begin until after the tumor has a network of blood vessels. In addition, both angiogenesis and metastasis require MMPs, enzymes that break down the surrounding tissue (the extracellular matrix) during blood vessel and tumor invasion.
Of the anti-angiogenic drugs now in clinical trials, some were designed to target specific molecules involved in new blood vessel formation while others work directly to inhibit endothelial cell function or response. For some, the exact mechanism of action of the drug is not known, but it has been shown to be anti-angiogenic by specific laboratory tests (in the test tube or in animals).
In general, four strategies currently are being used by investigators to design anti-angiogenesis agents:
- Block the ability of the endothelial cells to break down the surrounding matrix.
- Inhibit normal endothelial cells directly.
- Block factors that stimulate angiogenesis.
- Block the action of integrin, a molecule on the endothelial cell surface.
Standard Chemotherapy Versus Angiogenesis Inhibitors
Some of the differences between standard chemotherapy and anti-angiogenesis therapy are the result of angiogenesis inhibitors targeting dividing endothelial cells rather than tumor cells. Anti-angiogenic drugs are not as likely to cause bone marrow suppression, gastrointestinal symptoms, or hair loss -- symptoms characteristic of standard chemotherapy treatments. Also, since anti-angiogenic drugs may not necessarily kill tumors, but rather hold them in check indefinitely, the endpoint of early clinical trials may be different than for standard therapies. Rather than looking only for tumor response, it may be appropriate to evaluate increases in survival and/or time to disease progression.
Drug resistance is a major problem with chemotherapy agents. Most cancer cells are genetically unstable, more prone to mutations, and therefore likely to produce drug resistant cells. Since anti-angiogenic drugs target normal endothelial cells, which are genetically stable, drug resistance may not develop. So far, resistance has not been a major problem in long-term animal studies or in preliminary clinical trials.
Finally, anti-angiogenesis therapy may prove useful in combination with therapy directly aimed at tumor cells. Because each therapy is aimed at a different cellular target, the hope is that the combination will prove more effective. Early trials with such combinations are currently under way.