The Promise of Angiogenesis Inhibitors

Targeting angiogenesis for cancer treatment has distinct advantages over other forms of therapy.

Anti-angiogenic therapy is directed against normal endothelial cells which are genetically stable, so it is less likely that drug resistance will develop as with chemotherapeutic agents.

Research and development in this field has been driven largely by the desire to find better cancer treatments. Tumors can grow only if they form new blood vessels; by stopping the growth of blood vessels, scientists hope to shut off the means by which tumors can extend themselves and spread inside the body.

		Researchers are now asking if inhibiting angiogenesis can slow down or prevent the growth and spread of cancer cells in humans.

To answer this question, almost two dozen angiogenesis inhibitors are currently being tested in cancer patients. These inhibitors fall into several different categories, depending on their mechanism of action.

Some inhibit endothelial cells directly

• Endostatin
• EMD121974
• TNP-470
• Squalamine
• Combretastatin A4

Others inhibit the angiogenesis signaling cascade

• Anti-VEGF antibody - Avastin
• SU5416
• SU6668
• PTK787/ZK 22584

Some block the ability of endothelial cells to break down the extracellular matrix

• Marimistat
• AG3340 . COL-3
• Neovastat
• BMS-275291

What are the potential advantages of angiogenesis inhibitors?

	Mild side effects compared to some cancer drugs, and less toxicity to most healthy cells Tumors do not appear to develop the same resistance to angiogenesis inhibitors as the resistance some tumors develop to chemotherapy drugs Improved outcomes appear to result from varied combinations of angiogenesis inhibitors, chemotherapy, and radiation Long-term administration may result in increased survival Potential for preventing, slowing down, or blocking metastasis

What are the potential disadvantages of angiogenesis inhibitors?

The main disadvantage of angiogenesis inhibitor therapy is lifelong therapy may be required. When anti-angiogenic therapy is discontinued, dormant but viable foci of tumors can regain malignant and metastatic properties.

Also, angiogenesis inhibitors may not address all the proteins and small molecules that are involved in cell signaling and cancer growth. As a result, this therapy may provide incomplete and/or temporary inhibition of cancer.

Dosage and associated adverse effects are also problematic with angiogenesis inhibitors. The original goal of angiogenesis inhibitors was to choke a tumor to death by killing all of its blood vessels. However, the doses required to accomplish this are toxic to humans and cause intolerable adverse effects, including harm to normal blood vessels. Lower doses provide less efficacy than higher doses, and adverse effects still occur.

Summary

• AI's may not necessarily reduce or eliminate tumors, but instead keep tumors stable and dependent on the angiogenesis inhibitor.
• Improved outcomes appear to require combination treatments.
• Because angiogenesis is important in wound healing and reproduction it may cause problems with bleeding, blood clotting, heart function, the immune system, and the reproductive system.
• High cost
• Short-term efficacy

What is the availability of angiogenesis inhibitors?

Some angiogenesis inhibitors have been approved by the Food and Drug Administration for specific types of cancer, and are used "off-label" for other cancers.

• In June 2006, the FDA approved the drug Avastin in combination with intravenous 5-FU-based chemotherapy for 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).
• In July 2009, Avastin was approved for the treatment of metastatic renal cell carcinoma in combination with interferon alpha.

What is the future of angiogenesis inhibitors?

Researchers have answered many questions about angiogenesis, but many questions still remain. Scientists do not know whether using angiogenesis inhibitors to treat cancer will trigger unknown side effects, how long treatment will need to last, or whether tumor cells will find alternative routes for vascularization.

To answer such questions, human clinical trials are currently underway. Future research will evaluate the following:

	Angiogenesis inhibitors targeting multiple proteins and small molecules at the same time New combinations of cancer therapies with angiogenesis inhibitors Understanding other mechanisms involved in cancer growth associated with angiogenesis Types of people with cancer that are more likely to benefit from specific angiogenesis inhibitors Molecular and cellular characteristics that are present when angiogenesis inhibitors work and do not work in people

For More Information:

• Angiogenesis Inhibitors Clinical Trials (research studies in people)
• National Cancer Institute's Angiogenesis Inhibitors Therapy Fact Sheet
• National Cancer Institute Understanding Cancer Series: Angiogenesis