Ganging Up on Brain Metastases
Vorinostat, a histone deacetylase inhibitor, when coupled with radiation therapy, increased the survival time of the mice by almost 50 percent compared with untreated mice.
When primary tumors metastasize to the brain, the prognosis for patients is poor. The currently accepted treatment is whole-brain radiation therapy, and the median survival time is several months. Since these types of tumors form in 10 to 30 percent of adult cancer patients, improvements in treatment methods are a necessity.
Vorinostat is an anticancer drug that is currently undergoing clinical evaluation. It belongs to a class of drugs called histone deacetylase inhibitors. Histones are proteins that bind to DNA and package it into compact structures, thereby regulating gene expression. The interactions of histones with DNA are controlled in part by the addition or removal of acetyl groups from the histones by acetylases or deacetylases, respectively. Vorinostat inhibits the removal of the acetyl group by histone deacetylases, and drugs of this class have been shown to induce growth arrest, differentiation, and death of tumor cells.
Previous studies have shown that vorinostat also increases the susceptibility of cultured tumor cells to radiation. However, this advantageous effect has not been reported in live organisms. Andrew Baschnagel, M.D., a clinical fellow working under Kevin Camphausen, M.D., branch chief of the NCI Radiation Oncology Branch, investigated the combined effect of radiation and vorinostat on several types of cancer cells, including metastatic breast cancer cells injected into mice. A report of the study was recently published in Molecular Cancer Therapeutics.
The researchers first looked at the radiation susceptibility of three types of cultured tumor cells after treatment with vorinostat. The three cell lines tested were derived from ovarian cancer, breast cancer, and breast cancer that had metastasized to the brain. In all three cases, vorinostat was effective at increasing susceptibility to radiation.
The metastatic tumor cells were also used to determine the molecular basis for the increase in radiation susceptibility. The researchers found that treatment with vorinostat renders cells unable to repair the double-strand DNA breaks induced by radiation. When both strands of DNA are broken at the same place, the effects can be disastrous. When the cell divides, the compromised chromosome will be pulled apart; these catastrophic events generally lead to cell death.
While the greater than additive effect of radiation and vorinostat observed in cell culture is a good first step, it is important to show that the drug can influence tumor cells in a living organism. To measure the effects on tumor growth, metastatic breast cancer cells were injected into the leg of a mouse. After exposure to vorinostat and radiation treatment, the cancer cells grew at half the rate of untreated cancer cells. The effects of the treatment on metastasis were simulated by implantation of metastatic breast cancer cells into the skulls of mice. Under these conditions, vorinostat coupled with radiation therapy increased the survival time of the mice by almost 50 percent compared with untreated mice. In both cases, the positive effects of using vorinostat and radiation treatment together were greater than for either treatment alone.
Approximately 20 to 30 percent of brain metastases originate from breast cancer. The demonstration that vorinostat coupled with radiation therapy is able to retard the growth of metastatic breast cancer cells in vivo and improve survival of mice with brain metastases is a positive step toward improved treatment for a group of patients who currently have few options.Summary Posted: Mon, 06/01/2009
Mol Cancer Ther. 2009 Jun;8(6):1589-95. PubMed Link