OncoLog

 

From OncoLog, June 2012, Vol. 57, No. 6

VEGF Inhibitors: Promise and Challenges

By Stephanie Deming

All of the antiangiogenic agents approved by the U.S. Food and Drug Administration for cancer treatment primarily target vascular endothelial growth factor (VEGF), a powerful regulator of the development and function of blood vessels in tumors.

Since VEGF’s discovery nearly 30 years ago, basic science and clinical researchers have been studying how blocking VEGF might slow or stop the growth of tumors, which require a blood supply to survive and expand. Lee Ellis, M.D., a professor in the Departments of Surgical Oncology and Cancer Biology, ad interim chair of the Department of Cancer Biology, and director of the Metastasis Research Center at The University of Texas MD Anderson Cancer Center, began conducting research in the field of antiangiogenic therapy in 1992. Since then, he has seen tremendous initial excitement about antiangiogenic agents give way to measured optimism, or even cynicism, based on clinical trial results. “The improvement in patient outcomes with these drugs is variable,” he said, “but it is less than we had anticipated.”

In 2003, the first phase III clinical trial of a VEGF inhibitor, bevacizumab, showed that the agent’s addition to standard chemotherapy for metastatic colorectal cancer increased overall survival by an average of 4 months. To date, it is estimated that more than 30 VEGF inhibitors have been identified and tested in more than 2,000 clinical trials.

Today, five VEGF inhibitors are approved by the U.S. Food and Drug Administration for cancer treatment: bevacizumab for non–small cell lung cancer, recurrent glioblastoma, metastatic colorectal cancer, and metastatic renal cell carcinoma (RCC); sunitinib for advanced RCC and advanced pancreatic neuroendocrine tumors; pazopanib for advanced RCC and advanced soft tissue sarcoma; axitinib for advanced RCC; and sorafenib for advanced RCC and unresectable hepatocellular carcinoma.

Bevacizumab, probably the best-known VEGF inhibitor, is a monoclonal antibody that binds to VEGF and thereby prevents VEGF from binding to VEGF receptors. It is given intravenously once every 2–3 weeks. Pazopanib, axitinib, sunitinib, and sorafenib are tyrosine kinase inhibitors that block VEGF-induced cellular signaling. These drugs are taken orally, typically once or twice a day.

Reviewing the current knowledge of VEGF inhibitor therapy, Dr. Ellis said that one of the most important findings to date is that in most types of cancer, including those of the colon, breast, and lung, VEGF inhibitors confer no benefit unless they are administered in combination with chemotherapy. Another important finding is that VEGF inhibitors produce side effects such as hypertension and, rarely, bleeding problems and blood clots.

“I think we’ve kind of hit a ceiling in designing new VEGF inhibitors,” Dr. Ellis said. “There are only two ways to improve VEGF inhibitor therapy: one is to find predictive biomarkers that indicate which patients are going to respond and which are not, and the other is to figure out how best to use VEGF inhibitors in combination with other therapies. Identifying which patients are most likely to respond is important because we do not want to administer a drug to a patient if we know it will not be effective.”

Researchers are looking for biomarkers that could be measured to identify likely responders before treatment. At the European Society of Medical Oncology meeting in October 2011, researchers revealed evidence that circulating levels of a form of VEGF-A predicted response to bevacizumab in patients with glioblastoma. However, it is not clear precisely what level of VEGF-A should be used as the cut-off to distinguish which patients are likely to benefit. Furthermore, these results came from a retrospective study and need to be validated prospectively.

The search for other predictive biomarkers is made difficult by the fact that the mechanisms of action of VEGF inhibitors remain unclear. “It’s likely that the mechanisms of action are dependent on the specific tumor type,” Dr. Ellis said. A number of theories have been proposed to explain how these drugs work, including that the drugs inhibit angiogenesis, inhibit vasculogenesis, normalize the tumor vasculature, constrict blood vessels, alter the stem cell niche, or exert immunologic effects. In any case, inhibition of angiogenesis (i.e., blocking the proliferation of endothelial cells, which form blood vessels) does not appear to be the sole explanation for the drugs’ effects.

Dr. Ellis believes that VEGF inhibitors should continue to be tested in combination with various types of drugs, including other antiangiogenic therapies, signaling inhibitors, and chemotherapy drugs.

“We have to keep an open mind, but we shouldn’t use a shotgun approach,” said Dr. Ellis, who is currently studying the role of VEGF receptors on colon cancer cells. “We should take a very measured and scientific approach based on validated, preclinical data that support clinical trial development.”

For more information, contact the Office of Physician Relations at 713-792-2202.

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