The proteasome inhibitor bortezomib (Velcade) kills malignant glioma cells and can enhance the ability of tamoxifen to do the same, NCI researchers reported last week at the American Association of Cancer Research (AACR) annual meeting in Washington, D.C. The findings, the researchers said, lend further support to the rationale behind a phase II clinical trial launched nearly 1 year ago that is testing bortezomib and tamoxifen in patients with recurrent, high-grade malignant gliomas.

There has been little progress in the treatment of gliomas, the most common type of brain cancer, over the past two decades; the median survival for those with the most aggressive and most common glioma, glioblastoma, is a little more than a year. Tamoxifen, a selective estrogen receptor modulator, or SERM, is primarily used to treat or prevent breast cancer in women at high risk for the disease. During the last 10 to 15 years, however, tamoxifen also has been a last option after standard treatments have failed in some glioma patients, said Dr. Howard Fine, of NCI's Center for Cancer Research, and has demonstrated a clinical benefit in some patients.

The current phase II trial, being conducted at the NIH Clinical Center, follows a series of studies conducted in Dr. Fine's lab over several years in which researchers have demonstrated the important role of the intracellular protein NF-κB in glioma cell survival, and that inhibition of NF-κB could enhance the glioma cell-killing activity of tamoxifen and at least one other investigational SERM.

Although tamoxifen induces breast cancer cell death by inhibiting the estrogen receptor, studies by Dr. Fine's lab and others have shown that it kills glioma cells even though those cells do not express the estrogen receptor.

In the study results presented at AACR, NF-κB was highly active in glioma cell lines but never in normal tissue, explained the study's leader, Dr. Ai-Min Hui. And gene-expression profiles on 203 glioma clinical samples revealed that other genes activated by NF-κB were upregulated, which was not the case in healthy samples.

Glioma cells appear intrinsically to always be on the verge of death, Dr. Fine added, and NF-κB seems to play an essential role in keeping them alive, acting like a full-time security system.

"The glioma tumor cells are not just turning NF-κB on in response to stress," he said. "They have this pathway overexpressed all of the time to be able to resist any stress, including chemotherapy or radiation therapy. It's probably one of the reasons gliomas are so resistant to treatment."

Dr. Fine's lab started testing bortezomib, which is approved for use in patients with multiple myeloma, because it's been shown to inhibit NF-κB. The proteasome is a large conglomeration of proteins, known as a complex, inside cells that is responsible for breaking down damaged or unneeded proteins. Bortezomib promotes cancer cell death by disrupting this essential regulatory process which, as a welcome side effect, disrupts NF-κB expression.

In this new study, Dr. Hui explained, they determined that bortezomib's ability to disrupt NF-κB is actually achieved by blocking the activity of another protein that regulates NF-κB's function, IκB-alpha.

Dr. Fine's lab also has found that bortezomib can enhance the cell-killing activity of radiation and chemotherapy.

In addition to the phase II trial at the NIH Clinical Center, the NCI-funded New Approaches to Brain Tumor Therapy Consortium is conducting a phase I/II trial testing bortezomib alone in patients with malignant gliomas for whom standard therapies have failed.

By Carmen Phillips