Glioblastoma is the most common and deadliest form of brain cancer. A factor contributing to treatment failure is that these malignant cells are sneaky—they develop the ability to hide from the drugs designed to target them. Researchers at UCLA’s Jonsson Comprehensive Cancer Center (JCCC) have discovered how these cancer cells evade detection and become resistant to treatment. They published their findings online in the December 5 issue of the journal Science.
Drugs have been developed that seek out and kill glioblastoma cells targeting mutations on the cell surface that promote tumor growth. The researchers discovered that the tumor cells are able to eliminate the gene mutation; thus, removing the target while the drug is present. They also found that when the drug is no longer present in the body, the malignant cells reacquire the gene mutation (called an oncogene) that helps them grow more vigorously. As a result, the glioblastoma cells can eliminate the oncogene identified by drugs that specifically target them and regain the oncogene after the treatment is concluded. However, of significant importance is that the malignant cells’ dynamic ability to reacquire this oncogene makes them susceptible to the original therapy. “Now that we know that tumor cells have the surprising capacity to lose this oncogene during treatment and then reverse the process after drug removal, we may be able to exploit this phenomenon in the clinic,” explained first author David Nathanson, assistant professor of Molecular and Medical Pharmacology at UCLA.
In addition to the discovery promoting treatment methods for glioblastoma, the therapy may be applicable other malignancies that are susceptible to oncogene elimination. The researchers note that this study is the first to show reversible loss of an oncogene causing drug resistance; thus, it could lead to different and more effective approaches to treat these cancers.
The research was supported by The Ben and Catherine Ivy Foundation Fund, the National Institutes of Health, the Ziering Family Foundation, Art of the Brain Fund, the James S. McDonnell Foundation, The European Commission, the Ruth L. Kirschstein Institutional National Research Service Award, the UCLA Scholars in Oncologic Molecular Imaging Program, and the Ludwig Institute for Cancer Research.
Glioblastomas are tumors that arise from astrocytes, which are the star-shaped cells that comprise the “glue-like,” or supportive tissue of the brain. These tumors are usually highly malignant because the cells reproduce quickly and they are supported by a large network of blood vessels. Because these tumors can grow rapidly, the most common symptoms are usually caused by increased pressure in the brain. These symptoms can include headache, nausea, vomiting, and drowsiness. Depending on the location of the tumor, patients can develop a variety of other symptoms such as weakness on one side of the body, memory and/or speech difficulties, and visual changes. The risk of developing a glioblastoma increases with age and affects more men than women. Only 3% of childhood brain tumors are glioblastomas.