Vascular Endothelial Growth Factor (VEGF) Inhibitors, Recent Developments in Cancer Treatment

Most of the FDA-approved antiangiogenesis drugs like Bevacizumab (Avastin), Cetuximab and Panitumumab (INN), formerly ABX-EGF; work by blocking endothelial growth factor receptor (EGFR), which in tern inhibit vascular endothelial growth factor (VEGF), which directly stimulates blood vessel development in tumours.

A diagnostic immunohistochemistry assay can be used to detect EGFR expression in the tumor material. Approximately 75% of patients with metastatic colorectal cancer have an EGFR-expressing tumor.

Bevacizumab is currently approvedby the U.S. Food and Drug Administration (FDA) for cancers that are metastatic (have spread to other parts of the body). It received its first approval in 2004 for combination use with standard chemotherapy for metastatic colon cancer and non-small cell lung cancer.

In 2008, the FDA approved bevacizumab for use in metastatic breast cancer. This was controversial, because the FDA's advisory panel recommended against approval, since it only slowed tumor growth but failed to extend survival. In July 2010, the FDA revoked the indication for advanced breast cancer.

Bevacizumab inhibits the growth of blood vessels, which is part of the body's normal healing and maintenance. The body grows new blood vessels in wound healing, and as collateral circulation around blocked or atherosclerotic blood vessels. One concern is that bevacizumab can interfere with these normal processes, and worsen conditions like coronary artery disease or peripheral artery disease.

The main side effects are hypertension and heightened risk of bleeding. Bowel perforation has been reported. In advanced lung cancer, less than half of patients qualify for treatment. Posterior reversible encephalopathy syndrome, nasal septum perforation, and renal thrombotic microangiopathy have been reported. In December 2010, the FDA warned of the risk of developing perforations in the body, including in the nose, stomach, and intestines.

Cetuximab is indicated for the treatment of patients with squamous cell carcinoma of the head and neck in combination with platinum-based chemotherapy for the 1st line treatment of recurrent and/or metastatic disease and in combination with radiation therapy for locally advanced disease.

One of the more serious side effects of Cetuximab therapy is the incidence of acne-like rash. This rash rarely leads to dose reductions or termination of therapy and is generally reversible.

There can be severe infusion reactions like fevers, chills, rigors, urticaria, pruritis, rash, hypotension,  bronchospasm, dyspnea, wheezing, angioedema, dizziness, anaphylaxis, and cardiac arrest. Other common side effects include photosensitivity, hypomagnesemia due to magnesium wasting; and less commonly pulmonary and cardiac toxicity.

Panitumumab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory EGFR-expressing metastatic colorectal cancer in patients with non-mutated (wild-type) KRAS".

However, the above drugs targeting the VEGF pathway can "normalize" tumor vasculature and improve the effectiveness of other therapies, but in addition to their limited effect on patient survival, such agents also can generate resistance or have toxic effects.

Although these drugs have become standard treatments for several types of cancer, they only provide modest benefit in terms of extending patient survival, so more effective drugs targeting tumor vasculature are needed.

Massachusetts General Hospital researchers have discovered the first of an entirely new class of antiangiogenesis drugs/agents that interfere with the development of blood vessels.

In a report in Proceedings of the National Academy of Sciences/Early Edition, the investigators describe how a compound derived from a South American tree was able, through a novel mechanism, to interfere with blood vessel formation in animal models of normal development, wound healing and tumor growth.

One of two compounds identified by this process was dehydro-alpha-lapachone (DAL), derived from Tabebuia avellanedae, a tree native to Argentina and Brazil. Since DAL has structural similarities to another agent with antitumor activities and did not appear to be toxic, it was chosen for further investigation.

The researchers first showed that DAL administration interfered with blood vessel formation in zebrafish, both during embryonic development and wound healing. They then found that it reduced the vascular density of tumors implanted in mice and, with daily treatment, significantly reduced tumor growth with no signs of toxicity.

Experiments with endothelial cells from human umbilical veins revealed that DAL administration altered the size and shape of the cells by changing the organization of the actin cytoskeleton; blocked formation of new vascular networks and reorganized existing networks; and interfered with the movement of cells required for wound healing.

Further investigation found that DAL produces these effects by decreasing the activity of Rac1, a protein known to be important to cellular adhesion and cytoskeletal organization.

"DAL has the potential to improve treatment of many types of cancer and of other diseases characterized by abnormal blood vessels"; the researchers conclude.