Angiogenesis inhibitors: New cancer drugs stop tumor growth

As with all living things, even cancer needs oxygen and nutrients to help it grow and thrive. To get the fuel they need, tumors develop a network of new blood vessels in a process called angiogenesis. Angiogenesis is an area of intense focus by cancer researchers who hope that stopping angiogenesis could mean stopping cancer from growing and spreading.

Numerous drugs that may one day help prevent, stop or reverse angiogenesis are under investigation. These drugs are referred to as angiogenesis inhibitors or anti-angiogenic drugs. Only one drug that acts solely as an angiogenesis inhibitor is currently approved for use, but researchers are finding that many cancer drugs intended to attack cancer cells in other ways may also act as angiogenesis inhibitors. Researchers hope that stopping or reversing angiogenesis could leave tumors small and manageable.

What is angiogenesis?

Angiogenesis describes the formation of new blood vessels within your body. For instance, an embryo uses angiogenesis to develop inside the womb, a woman experiences angiogenesis as a normal part of menstruation, and body tissues use angiogenesis to help heal wounds.

Angiogenesis also refers to the process by which a tumor develops a blood supply. Small tumors can survive without a network of blood vessels to deliver oxygen and nutrients. These small tumors rely on nearby tissue to deliver small amounts of energy.

In order to grow larger and spread (metastasize), a tumor needs its own blood supply. Blood vessels give a tumor the oxygen and nutrients it needs to maintain rapid growth. Blood vessels also offer access to other areas of the body. Without a blood supply, a tumor remains very small and localized.

What causes angiogenesis in tumors?

Angiogenesis begins when your body's own defenses can no longer hold back a tumor's growth signals. Your body naturally makes chemicals that prevent angiogenesis from occurring when it isn't needed. This keeps tumors very small — less than a few millimeters in size, or about the size of a pencil eraser. Researchers aren't sure what happens to throw off the balance of power between your body and the tumor. Whether the tumor's growth signals become stronger or something happens to weaken your own defenses, the result is what's called the "angiogenic switch." This term refers to the change from a small, localized tumor to a growing, spreading cancer.

How does angiogenesis occur?

Once the angiogenic switch has been turned on, the tumor begins sending out signals to the cells lining nearby blood vessels (endothelial cells). These signals cause the endothelial cells to grow and multiply. The endothelial cells direct enzymes to clear a pathway to the tumor. The blood vessels form stems that reach to the tumor. Once the blood vessel stems connect, the tumor uses the new blood vessels to receive oxygen and nutrients. It also sends out cancer cells to spread elsewhere in the body.

Much like cancer cells themselves, a tumor's blood supply grows out of control and without order. Your body's normal, healthy blood vessels are organized in a logical, orderly way. A tumor's blood vessels are mangled and twisted.

How can angiogenesis be stopped?

Researchers are investigating a number of ways to stop or alter the angiogenesis process, including:

• Blocking initial signals from the tumor. A tumor sends out signals, called growth factors, to stimulate the endothelial cells to start making new blood vessels. A number of these signals exist, each working in its own way to connect new blood vessels to the tumor. Some tumors send out several different signals. Others may send out only one or two. The most common signal is vascular endothelial growth factor (VEGF).

  The only signal-blocking angiogenesis inhibitor currently available is bevacizumab (Avastin), which is approved to treat colon cancer. Bevacizumab intercepts a tumor's VEGF signals and stops them from connecting with the endothelial cells.

• Making initial signals from the tumor less effective. When a tumor sends out VEGF signals, those chemicals attach to receptors on the endothelial cells. The endothelial cells read the signal and begin to multiply. Drugs that clog those receptors stop VEGF from attaching and completing its mission. Other drugs, called small molecule drugs, can get inside the endothelial cells and stop the cells from acting on the signals.

  Two small molecule drugs that interfere with a receptor called tyrosine kinase have been approved for use. Sorafenib (Nexavar) was approved in late 2005 to treat kidney cancer. Sunitinib (Sutent), for kidney cancer and gastrointestinal stromal tumors (GIST), was approved in early 2006.

• Stopping the enzyme pathway. The enzymes that clear a pathway for blood vessels to extend to the tumor are also targets of angiogenesis inhibitors. Without the pathway, the endothelial cells can't connect to the tumor. This stops the formation of blood vessels.
• Normalizing mangled blood vessels. When a tumor has already attracted a network of blood vessels, it may be possible to rearrange or normalize those blood vessels. Some researchers believe angiogenesis inhibitors could do this, making an easier route to deliver chemotherapy and other cancer treatments to the tumor. That would explain why angiogenesis inhibitors are usually more effective when combined with chemotherapy.
• Preventing the switch from turning on. Some genes that turn normal cells into cancer cells (oncogenes) have been found to also play a role in causing the angiogenesis process to begin. Drugs that target these oncogenes could prevent the angiogenic switch from being turned on, keeping a tumor small and dormant. Examples include gefitinib (Iressa), approved for use in lung cancer, and cetuximab (Erbitux), approved for use in colon cancer and head and neck cancers.

It's possible for a single drug to work on more than one aspect of the angiogenic process.

Other drugs have been found to interfere with angiogenesis, though they weren't originally developed for that reason. Examples include chemotherapy drugs such as paclitaxel (Taxol) and cyclophosphamide (Cytoxan, Neosar), COX-2 inhibitors such as celecoxib (Celebrex), and thalidomide (Thalomid).

What's in the future for angiogenesis research?

Researchers hope a better understanding of the angiogenesis process will help them target treatments to different cancers. One day a treatment could be devised for you based on the growth factors your cancer uses to cause angiogenesis. A specific combination of angiogenesis inhibitors, possibly combined with chemotherapy, could be used to stop your cancer from growing.

Researchers are also investigating ways to alter the way a tumor interacts with the lymph system. Similar to how a tumor attracts blood vessels, a tumor can also attract lymph vessels — a process called lymphangiogenesis. Lymph vessels are part of your lymphatic system, which clears bacteria, viruses and waste products from your body. Your lymphatic system provides another way for cancer to spread. One day, doctors may be able to stop both methods of angiogenesis, effectively stopping cancers' ability to spread.

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