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With the support of grant funding from the National Institutes of Health (NIH), researchers at Virginia Commonwealth University Massey Cancer Center are hard at work investigating a new "synthetically lethal" strategy for treating glioblastoma multiforme (GBM), the most common and deadly form of brain cancer.

GBM is almost always lethal, with a mean survival time of only 12-15 months after diagnosis. Furthermore, standard treatments often result in significant cognitive impairment due to the sensitive nature of the brain. Kristoffer Valerie, Ph.D., co-leader of the Radiation, Biology and Oncology program and a professor in the Department of Radiation Oncology at VCU Massey Cancer Center, is testing a relatively new strategy known as synthetic lethality that may have the potential to treat the cancer while sparing healthy brain tissue. Synthetically lethal drug combinations work by blocking DNA repair and other survival pathways in tumor cells. The treatment is not fatal to healthy cells, but is lethal to tumor cells that might already have mutations in other DNA repair genes. As a result, breaks in the cells' DNA cannot be repaired and the tumor cell dies.

"The brain consists mainly of cells that do not proliferate. Glioblastomas, however, are fast growing and invasive tumors. Our proposed treatment focuses on blocking the tumor cells' ability to repair DNA damage and to continue multiplying," says Valerie. "At the same time, we have to keep a very close eye on protecting those brain cells that do have the ability to grow and renew brain function, such as brain stem cells and neural progenitors. We feel our strategy could be a promising new solution."

 The NIH grant, designed to support exploratory and therapeutic cancer research, will fund Valerie's proposed multi-pronged treatment strategy for GBM. Using mouse tumor models, Valerie and his team will test a combination of synthetically lethal small molecule inhibitors in conjunction with radiation therapy. The first drug, AZD2281, also known as Olaparib, inhibits the enzyme poly (ADP) ribose polymerase (PARP), which is important for repairing DNA single-strand breaks in cells. The other drug, KU-60019, targets the DNA damage sensor ATM (ataxia telangiectasia mutated) that controls cellular functions important for detecting and initiating repair of DNA double-strand breaks, and has been previously shown to sensitize glioma cells to radiation and reduce cancer progression and invasion. Radiation will be used to increase the anti-tumor effects of the treatment, as radiation causes additional DNA damage that the tumor cells will be ill-equipped to repair due to the drugs' effects.

Ultimately, the researchers hope that, through these experiments, they will establish proof-of-concept in order to provide the rationale for a Phase I clinical trial testing this treatment in GBM patients.

 "As treatment improves and patients live longer, cognitive ability and quality of life becomes increasingly important," says Valerie. "We need to find better ways to treat this devastating disease while sparing the rest of the brain."

Written by: John Wallace