EphA2 represents a promising treatment target for glioblastoma multiforme

Nov 1 2005

Researchers at Wake Forest University Baptist Medical Center have identified a second promising treatment target for glioblastoma multiforme, one of the most deadly types of brain tumors. The research results are reported in the October issue of Molecular Cancer Research.

"We've found that a particular protein may play a major role in the progression of these tumors, suggesting an attractive new treatment approach," said Waldemar Debinski, M.D., Ph.D., director of the Brain Tumor Center of Excellence at Wake Forest University Baptist Medical Center.

This was the first study to investigate the presence and significance of a protein called EphA2 in brain cancer cells. This protein, which is found in cell membranes, allows normal cells to communicate with their environment and each other. In its normal active state, the protein seems to inhibit abnormal cell growth and division.

Debinski and colleagues demonstrated that glioblastoma cells have significantly increased levels of the protein EphA2 compared to normal cells – but it is in an inactive form. They believe that this inactive form of EphA2 aids in the survival and spread of cancer cells.

To test their hypothesis, they treated glioblastoma cells with ephrinA1, a naturally occurring molecule that binds to EphA2 and activates it. They had already demonstrated that ephrinA1 is present at much lower levels in cells and tumors with increased levels of inactive EphA2.

"We observed that cells treated with ephrinA1 slowed down their growth and were less likely to exhibit invasive properties," said Debinski.

The researchers believe that developing medication to change levels of EphA2 and ephrinA1 offers new promise for successfully treating glioblastoma multiforme, which is the most common form of brain tumor and the least curable of all human cancers. The majority of the 17,500 brain tumors diagnosed each year in the United States are glioblastomas. Patients have a median survival time of nine to 12 months and a five-year survival rate of 1 to 5 percent.

"EphA2 represents a novel target for the development of molecular therapeutics for the imaging and treatment of patients with glioblastoma," said Debinski. "New therapies are clearly needed because, despite the standard treatment of surgically removing the tumor and treating the patient with chemotherapy and radiation, survival has increased only slightly over the past 30 years."

Debinski has already developed one treatment for glioblastoma, based on his discovery that the tumor's cells have a particular type of receptor for interleukin 13 (IL 13), a naturally occurring protein that regulates the immune system in the body. Normal cells do not have these same receptors. Debinski developed a drug that combines a form of IL-13 with a toxin that kills cancer cells. By targeting the therapy to these receptors, the drug finds and kills the cancer cells. The first generation of the drug is being tested in advanced clinical trials worldwide.

Both of Debinki's projects focus on the identification of "molecular markers," or molecules that are found in high levels on tumor cells but are nearly absent on normal cells. This makes them attractive for such treatment approaches as targeted drug delivery.

EphA2 may also show promise for treating other types of cancer. It has been shown to be present at high levels in several other tumors, such as pancreas, colon and breast. And recently other researchers have shown that EphA2 is a potential target for a glioblastoma vaccine that could potentially prevent recurrences of the tumors.

Debinski's results were preliminarily reported at the World Federation of NeuroOncology meeting and the European Association for Neuro-Oncology meeting, both in Edinburgh, Scotland, in May. Jill Wykosky, B.S., and Denise Gibo, B.S., from Debinski's laboratory, conducted this work, and Constance Stanton, M.D., from the Department of Pathology, collaborated.