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Blocking DNA Repair Mechanisms may Improve Radiation Therapy for Brain Cancer

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Based on a recent study, researchers at the UT Southwestern Medical Center have exhibited in both cancer cell lines and in mice that blocking vital DNA repair mechanisms could improve the overall efficiency of radiation therapy (RT) for often fatal brain tumors known as glioblastomas.

RT leads to double-strand breaks in DNA that must be repaired for tumors to keep growing. Scientists have long theorized that if they could find a way to block or obstruct repairs from being made, they then could prevent tumors from developing or at least slow down the growth, thus extending patients' survival. Blocking DNA repair is a particularly appealing tactic for treating glioblastomas, as these tumors are known to be highly resistant to RT. In the study, UT Southwestern researchers demonstrated that the theory does in fact work when placed in the context of glioblastomas.

"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 Associate Professor of Radiation Oncology in the division of Molecular Radiation Biology at UT Southwestern Dr. Sandeep Burma.

Burma’s lab works on understanding basic mechanisms by which DNA breaks are mended, with the main objective of improving cancer therapy with DNA damaging agents. Recent research from his lab has shown how a cell makes the choice between two major trails that are used to fix DNA breaks - non-homologous end joining (NHEJ) and homologous recombination (HR). His lab discovered that enzymes involved in cell division called cyclin-dependent kinases (CDKs) set off HR by phosphorylating a major protein, EXO1. In this scenario, the use of HR is joined to the cell division cycle, which has significant signs for cancer therapeutics. The study’s findings were published in the April issue of Nature Communications.

While the study explains how the cell chooses between NHEJ and HR, a translational study from the Burma lab shows how blocking both repair pathways can improve RT of glioblastomas. Researchers in the lab first were able to demonstrate in glioblastoma cell lines with a drug called NVP-BEZ235, which is undergoing clinical trials for other solid tumors, can also hamper two major DNA repair enzymes, DNA-PKcs and ATM, which are vital for NHEJ and HR, respectively. While the drug alone had a limited effect, when joined with RT, the tumor cells could not hastily mend their DNA, stunting their growth.

While understandably encouraged by the preliminary findings in cell lines, the researchers remained vigilant due to previous efforts to identify DNA repair inhibitors was unsuccessful when applied in living organisms, mice with glioblastomas. In addition, drugs developed to treat brain tumors must also go through, what's known as the blood-brain-barrier in living organisms.

However, the NVP-BEZ235 drug could successfully cross the blood-brain-barrier, and when administered to mice with glioblastomas in accordance with radiation, the tumor growth in mice was stalled and the mice survived for much longer , up to 60 days as opposed to around 10 days with the drug or RT alone. The findings were published in a recent issue of Clinical Cancer Research.

"The consequence is striking," remarked Burma. "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."

The combination effect is key because the standard therapy for glioblastomas in humans RT, therefore discovering a drug that enhances overall efficiency of RT could eventually have significant clinical importance. For instance, such drugs may allow lower doses of X-rays and gamma rays to be used for conventional therapies, thus causing fewer side effects.

"Radiation is still the mainstay of therapy, so we have to have something that will work with the mainstay of therapy," said Burma.

While the findings provide evidence that the notion of "radiosensitizing" glioblastomas works in mice, further research and clinical trials will be needed in order to demonstrate whether the combination of radiation with DNA repair inhibitors would be effective in humans, Burma warned.

"Double-strand DNA breaks are a double-edged sword. On one hand, they cause cancer. On the other, we use ionizing radiation and chemotherapy to cause double-strand breaks to treat the disease,” he said.
Another recent publication from his lab highlights this apparent paradox by demonstrating how radiation can actually trigger glioblastomas in mouse models. This research, supported by NASA, is focused on understanding cancer risks from particle radiation, the type faced by astronauts on deep-space missions and now being used in cutting-edge cancer therapies such as proton and carbon ion therapy.

Burma's lab uses the high-tech facilities and large particle accelerator of the NASA Space Radiation Laboratory at the Brookhaven National Laboratory in New York to produce heavy ions, which can be utilized to irradiate glioblastoma-prone mice to test both the cancer-inducing potential of particle radiation as well as its potential therapeutic use.

"Heavy particles cause dense tracks of damage, which are very hard to repair. 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," noted Burma

“These findings, published March 17 in Oncogene, suggest that glioblastoma risk from heavier particles is much higher compared to that from gamma or X-rays. This study is relevant to the medical field, since ionizing radiation, even low doses from CT scans, have been reported to increase the risk of brain tumors,” he said.

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