Three groundbreaking studies from the laboratory of Dr. Sandeep Burma, an associate professor in the Molecular Radiation Biology division of UT Southwestern Medical Center, may have directly translatable results for the treatment of glioblastomas, or notoriously difficult-to-treat aggressive brain tumors. It has long been theorized that inhibiting double-strand DNA break repair in tumor cells after radiation therapy may prevent tumors from growing further and enable patients to survive longer. Dr. Burma’s research group aimed to test this theory in the context of glioblastomas with hopes to advance treatment of glioblastomas because they are highly resistant to radiation therapy.
First, the Burma laboratory investigated how a cell chooses between two mechanisms of fixing double strand DNA break repair. They found that the choice of non-homologous end joining (NHEJ) vs. homologous recombination (HR) is made by cyclin-dependent kinases (CDKs), which activate the HR pathway by phosphorylating the protein EXO1. The involvement of CDKs means that HR is implicated during cell division, making the HR pathway vital to cancer cells that want to proliferate following radiation therapy. “This work is informative because the findings show that blocking the repair of DNA double-strand breaks could be a viable option for improving radiation therapy of glioblastomas,” said Dr. Burma. This paper was published in Nature Communications.
After making this basic discovery, the Burma lab moved on to test how blocking both NHEJ and HR improves radiotherapy of glioblastomas. They administered the drug NVP-BEZ235, which is under evaluation in clinical trials to treat other types of solid tumors, to mice with glioblastomas to inhibit the DNA repair enzymes DNA-PKcs (involved in NHEJ) and ATM (involved in HR). Initially, the scientists were worried that the treatment would not work–although in cell culture experiments, tumor growth was inhibited–because NVP-BEZ235 must cross the blood-brain-barrier to reach the mouse glioblastomas. Fortunately, NVP-BEZ235 can cross the barrier, and when it was administered in conjunction with radiation therapy, the team saw a six-fold increase in length of survival of the mice. Mice receiving combined treatment survived for 60 days, and mice receiving either NVP-BEZ235 or radiation therapy alone survived for 10 days. These findings we published in Clinical Cancer Research.
“The consequence is striking,” commented Dr. Burma on the results of the study. “If you irradiate the tumors, nothing much happens because they grow right through radiation. Give the drug alone, and again, nothing much happens. But when you give the two together, tumor growth is delayed significantly. The drug has a very striking synergistic effect when given with radiation.” This fact gives the study translatability because “radiation is still the mainstay of therapy, so we have to have something that will work with the mainstay of therapy,” explained Dr. Burma. Additional studies are required before they can be used in human clinical trials, but the study provides proof of concept that radiosensitizing glioblastomas is effective in mice.
Along the same lines of treating glioblastomas, the Burma laboratory is working with NASA to investigate how heavy ions affect glioblastoma-prone mice. It is important for NASA to understand the risk astronauts face on deep-space missions, as encountered particle radiation may have cancer-inducing potential. “Heavy particles cause dense tracks of damage, which are very hard to repair,” stated Dr. Burma. “With gamma or X-rays, which are used in medical therapy, the damage is diffuse and is repaired within a day. If you examine a mouse brain irradiated with heavy particles, the damage is repaired slowly and can last for months.” On a more Earth-based note, the findings have importance because ionizing radiation, from sources such as CT scans, have been reported to increase the risk of brain tumors. Findings related to this research were published in Oncogene.