Vorinostat Shows Anti-cancer Activity In Recurrent Gliomas

Glioblastoma multiforme is a lethal primary brain tumor. The average survival of glioblastoma patients is 12-16 months. These tumors spread quickly to other parts of the brain, and because of this are difficult to treat and often recur. When the tumor recurs, treatment options are limited, and patients survive for an average of three to four months.

"Existing treatment interventions have minimal impact on the outcome of recurrent glioblastoma multiforme patients," Dr. Galanis says. "Using vorinostat to treat glioblastoma multiforme patients who have relapsed following surgery, radiation and chemotherapy, we found that 15 percent of the patients had no tumor recurrence for six months or longer following treatment initiation. The median overall survival of the patients enrolled on the trial was 5.7 months -- similar patient populations enrolled in prior NCCTG trials had a median overall survival of between 4 and 4.4 months."

This study was the first application of vorinostat in targeting brain cancer. Vorinostat is approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T cell lymphoma in patients who have failed two or more systemic therapies.

An additional group of patients in this study was treated with vorinostat prior to surgery, and a gene and protein analysis of their resected tumors was performed. This analysis confirmed increase in histone acetylation and showed gene changes indicating that vorinostat reaches the glioblastoma tumors and interferes with the target pathways. Dr. Galanis says the researchers plan to expand this analysis to all study patients. This will help define a patient population that has a higher likelihood of benefiting from treatment -- allowing treatment individualization in the future.

Vorinostat is the first FDA approved oral anti-cancer agent that inhibits an enzyme, histone deacetylase, that is closely associated with DNA in cells. By inhibiting the deacetylation of histones -- proteins that help organize the structure of DNA -- vorinostat alters the expression of several important genes and proteins resulting in tumor cell death and stopping tumor growth.

Dr. Galanis says that study findings indicate that vorinostat by itself shows anti-cancer activity in glioblastoma multiforme. Plans are ongoing to combine vorinostat with other drugs in future clinical trials for brain tumor patients.

This NCCTG study was supported by the National Cancer Institute, which in collaboration with Merck & Co., Inc. (Whitehouse Station, N.J.), provided vorinostat (Zolinza™) for use in this study to the Mayo oncologists and their NCCTG colleagues.

Other Mayo investigators contributing to this study were Kurt Jaeckle, M.D.; Jan Buckner, M.D.; Matthew Maurer; Caterina Giannini, M.D.; Matthew Ames, Ph.D.; and Joel Reid, Ph.D.