But insights into how that happens may lead to ways around it, researchers say
Temozolomide, a standard treatment for brain cancer, may boost the aggressiveness of surviving cancer cells, making tumor recurrence more likely, a new study suggests.
The research team, from Memorial Sloan-Kettering Cancer Center in New York City, have identified cells in brain tumors called gliomas that have stem cell-like qualities and are able to survive chemotherapy with the help of a particular protein. These surviving cells become drug-resistant, and may be the reason treatment for brain cancer is usually unsuccessful.
“Stem-like cells are found in brain tumors, and the mutations that occur in high-grade tumors promote the stem cell character of tumor cells,” explained lead researcher Dr. Eric Holland, director of Sloan-Kettering’s Brain Tumor Center. “Furthermore, the standard therapy for brain tumors — although beneficial against many of the tumor cells — actually promotes stem cell character in the cells that survive.”
The report is published in the March 6 issue of Cell Stem Cell.
According to the American Cancer Society, nearly 22,000 Americans were diagnosed with a malignant tumor of the brain or spinal cord in 2008, and more than 13,000 died from these cancers. Brain tumors also gained prominence this past year after Sen. Ted Kennedy (D-Mass.) was diagnosed with a particularly aggressive type of cancer known as a malignant glioma.
For the new study, Holland’s team looked at the role of the protein ABCG2, which is associated with resistance to drugs in brain cancer cells. This protein transports drugs across the cell’s membrane, which would otherwise shield the tumor cell from chemotherapy drugs, Holland explained.
The researchers isolated cells from mice and human cancer brain tumors called glioblastomas. Some of these cells appeared to have the ability to renew themselves and resist chemotherapy, the team found, and ABCG2 appears to be a marker for these resistant cells.
Holland’s group also identified how the protein helps tumor cells expel chemotherapy drugs.
“Current treatment for gliomas works for a while and then usually fails,” Holland said. “These findings might be partly the reason for that. There is more than one cell type in these tumors, and they respond differently to the therapy we treat people with.”
For example, the chemotherapy drug temozolomide — which is the standard treatment for gliomas — actually increased the number of drug-resistant cells. Because temozolomide doesn’t target ABCG2, it may render surviving cells more resistant to treatments that do target the ABCG2 protein, Holland theorized.
“Life is complicated; brain tumors are complicated, too,” he said.
Dr. Ronald Benveniste is an assistant professor of neurosurgery at the University of Miami School of Medicine. He believes the study has a real upside because it points to new, longer-lasting brain cancer treatments.
“Clinically, what we see with patients with glioblastoma is that after surgery, radiation and chemotherapy with temozolomide, they live longer and a subset of them will actually live a year, two years or even longer. And then pretty much 100 percent of the patients relapse and no one knows why,” Benveniste said.
This study identifies the mechanism by which this happens, he said. “When you treat mice with temozolomide they develop recurrent diseases even quicker, so temozolomide make the cells that survive act in a more aggressive manner,” Benveniste said.
“In the future, relapse after treatment with temozolomide could be prevented by inhibiting these pathways,” he speculated. “This could open doors to treatment. This is exciting stuff.”