Features Partner Sites Information LinkXpress
Sign In
Demo Company

Radiotherapy for Brain Cancer May Be Improved by Blocking DNA Repair Processes

By BiotechDaily International staff writers
Posted on 30 Apr 2014
Print article
Researchers have demonstrated in both cancer cell lines and mice that shutting down critical DNA repair processes could enhance the effectiveness of radiation therapy for highly fatal brain tumors called glioblastomas.

Radiation therapy causes double-strand breaks in DNA that must be fixed for tumors to keep growing. Scientists have long theorized that if they could find a way to block repairs from being made, they could prevent tumors from growing or at least slow down the growth, thereby extending patients' survival. Blocking DNA repair is a particularly attractive strategy for treating glioblastomas, as these tumors are highly resistant to radiation therapy. In a new study, University of Texas (UT) Southwestern Medical Center (Dallas, USA) researchers demonstrated that the hypothesis actually works 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 Dr. Sandeep Burma, associate professor of radiation oncology in the division of molecular radiation biology at UT Southwestern.

Dr. Burma researches the determination of basic mechanisms by which DNA breaks are repaired, with the translational objective of improving cancer therapy with DNA-damaging agents. Recent research from his lab has demonstrated how a cell makes the choice between two major pathways that are used to repair DNA breaks—non-homologous end joining (NHEJ) and homologous recombination (HR). His lab found that enzymes involved in cell division called cyclin-dependent kinases (CDKs) activate HR by phosphorylating a key protein, EXO1. In this manner, the use of HR is coupled to the cell division cycle, and this has important implications for cancer therapeutics. These findings were published April 7, 2014, in the journal Nature Communications.

Whereas this study describes how the cell chooses between NHEJ and HR, a translational study from the Burma lab demonstrates how blocking both repair pathways can improve radiotherapy of glioblastomas. Researchers in the lab first were able to show in glioblastoma cell lines that a drug called NVP-BEZ235, which is in clinical trials for other solid tumors, can also suppress two key DNA repair enzymes, DNA-PKcs and ATM, which are crucial for NHEJ and HR, respectively. While the drug by itself had limited effect, when combined with radiation therapy, the tumor cells could not quickly repair their DNA, stalling their growth.

Although enthusiastic by the early findings in cell lines, the scientists remained guarded because earlier efforts to identify DNA repair inhibitors were not successful when used in living models—mice with glioblastomas. Drugs developed to treat brain tumors also must cross what's known as the blood-brain-barrier in living models.

However, the NVP-BEZ235 drug could effectively cross the blood-brain barrier, and when given to mice with glioblastomas and combined with radiation, the tumor growth in mice was inhibited and the mice survived a lot longer, up to 60 days compared to approximately 10 days with the drug or radiation therapy alone. These findings were published in a recent issue of Clinical Cancer Research.

“The consequence is striking,” said Dr. 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 significant because the conventional therapy for glioblastomas in humans is radiation therapy; therefore, finding a drug that enhances the effectiveness of radiation therapy could have profound clinical importance eventually. For example, such drugs may permit lower doses of X-rays and gamma rays to be used for traditional therapies, thereby 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,” Dr. Burma said.

Whereas the findings provide evidence that the theory of “radiosensitizing” glioblastomas works in mouse models, additional research and clinical trials will be needed to show whether the combination of radiation with DNA repair inhibitors would be effective in humans, Dr. Burma cautioned. “Double-strand DNA breaks are a double-edged sword,” he said. “On one hand, they cause cancer. On the other, we use ionizing radiation and chemotherapy to cause double-strand breaks to treat the disease.”

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

These findings, published March 17, 2014, in the journal 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 computed tomography (CT) scans, have been reported to increase the risk of brain tumors, according to Dr. Burma.

Related Links:

University of Texas Southwestern Medical Center

Print article



view channel
Image: Left: Green actin fibers create architecture of the cell. Right: With cytochalasin D added, actin fibers disband and reform in the nuclei (Photo courtesy of the University of North Carolina).

Actin in the Nucleus Triggers a Process That Directs Stem Cells to Mature into Bone

A team of cell biologists has discovered why treatment of mesenchymal stem cells (MSCs) with the mycotoxin cytochalasin D directs them to mature into bone cells (osteoblasts) rather than into fat cells... Read more


view channel

Molecular Light Shed on “Dark” Cellular Receptors

Scientists have created a new research tool to help find homes for orphan cell-surface receptors, toward better understanding of cell signaling, developing new therapeutics, and determining causes of drug side-effects. The approach may be broadly useful for discovering interactions of orphan receptors with endogenous, naturally... Read more

Lab Technologies

view channel
Image: The new ambr 15 fermentation micro-bioreactor system was designed to enhance microbial strain screening applications (Photo courtesy of Sartorius Stedim Biotech).

New Bioreactor System Streamlines Strain Screening and Culture

Biotechnology laboratories working with bacterial cultures will benefit from a new automated micro bioreactor system that was designed to enhance microbial strain screening processes. The Sartorius... Read more


view channel

Purchase of Biopharmaceutical Company Will Boost Development of Nitroxyl-Based Cardiovascular Disease Drugs

A major international biopharmaceutical company has announced the acquisition of a private biotech company that specializes in the development of drugs for treatment of cardiovascular disease. Bristol-Myers Squibb Co. (New York, NY, USA) has initiated the process to buy Cardioxyl Pharmaceuticals Inc. (Chapel Hill, NC, USA).... Read more
Copyright © 2000-2015 Globetech Media. All rights reserved.