Corporate Banner
Satellite Banner
Scientific Communities
Become a Member | Sign in
Home>News>This Article

Blocking DNA Repair Mechanisms Could Improve Brain Cancer Therapy

Published: Saturday, April 12, 2014
Last Updated: Saturday, April 12, 2014
Bookmark and Share
The findings were published April 7 in Nature Communications.

UT Southwestern Medical Center researchers have demonstrated in both cancer cell lines and in mice that blocking critical DNA repair mechanisms could improve the effectiveness of radiation therapy for highly fatal brain tumors called glioblastomas.

Radiation therapy causes 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 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 study, UT Southwestern researchers demonstrated that the theory 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.

His lab works on understanding 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.

While the above basic 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 inhibit two key DNA repair enzymes, DNA-PKcs and ATM, which are crucial for NHEJ and HR, respectively. While the drug alone had limited effect, when combined with radiation therapy, the tumor cells could not quickly repair their DNA, stalling their growth.

While excited by the initial findings in cell lines, researchers remained cautious because previous efforts to identify DNA repair inhibitors had not succeeded 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.

But the NVP-BEZ235 drug could successfully cross the blood-brain-barrier, and when administered to mice with glioblastomas and combined with radiation, the tumor growth in mice was slowed and the mice survived far longer - up to 60 days compared to approximately 10 days with the drug or radiation therapy alone. These findings were published in the March 1 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 important because the standard therapy for glioblastomas in humans is radiation therapy, so finding a drug that improves 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.

While the findings provide proof that the concept of “radio sensitizing” glioblastomas works in mouse models, additional research and clinical trials will be needed to demonstrate 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.”

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.

Dr. 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 generate heavy ions, which can be used 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,” 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 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, Dr. Burma said.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,700+ scientific posters on ePosters
  • More Than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Researchers Develop Classification Model for Cancers Caused by KRAS
Most frequently mutated cancer gene help oncologists choose more effective cancer therapies.
Saturday, October 10, 2015
UT Southwestern Biochemist Receives NIH Early Independence Award
Dr. William Israelsen studies on hibernation may aid the fight against cancer.
Wednesday, October 07, 2015
UT Southwestern Geneticist to Receive Pearl Meister Greengard Prize
Dr. Helen Hobbs will receive the prize Nov. 17 in a ceremony at The Rockefeller University.
Tuesday, October 06, 2015
Physiologists Uncover a New Code at the Heart of Biology
New “code” - the speed limit of assembly - dictate the ultimate function of a given protein.
Thursday, September 24, 2015
CRI Scientists See Through Bones
Findings uncover new details about blood-forming stem cells.
Thursday, September 24, 2015
Researchers Assist in Landmark NIH Study
Study shows intensive blood pressure management may save lives.
Saturday, September 12, 2015
Regenerative Medicine Biologists Discover a Cellular Structure that Explains Fate of Stem Cells
The findings are presented in the journal Nature.
Thursday, July 02, 2015
Cell that Replenishes Heart Muscle Found by UT Southwestern Researchers
Researchers devise a new cell-tracing technique to detect cells that do replenish themselves.
Tuesday, June 23, 2015
Researchers Find Molecular Mechanisms within Fetal Lungs that Initiate Labor
Biochemists found that steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2) proteins control genes.
Tuesday, June 23, 2015
Researchers Discover Molecule that Accelerates Tissue Regeneration
Newly discovered molecule, SW033291 accelerate cell recovery following bone marrow transplants.
Friday, June 12, 2015
Boosting Gut Bacteria Defense System May Lead to Better Treatments
Life-threatening bloodstream infections reversed by enhancing a specific immune defense response.
Tuesday, June 09, 2015
Immunity Enzyme Defends Against Tuberculosis Infection
Study shows that cGAS enzyme is essential for defense against the tuberculosis bacteria.
Wednesday, June 03, 2015
UT Southwestern Faculty Members Named HHMI Investigators
Appointment of Dr. Kim Orth and Dr. Joshua Mendell to HHMI.
Saturday, May 23, 2015
UT Southwestern’s Dr. Philipp Scherer Receive Banting Medal
Dr. Scherer will receive the prestigious Medal for diabetes research.
Friday, May 08, 2015
Mutations in Two Genes Linked to Familial Pulmonary Fibrosis and Telomere Shortening
PARN and RTEL1 genes strengthen the link between lung fibrosis and telomere dysfunction.
Tuesday, May 05, 2015
Scientific News
Breaking Through the Barriers to Lab Innovation
Here we examine the drivers behind the move for greater innovation, the challenges and current trends in laboratory informatics, and the tools that can be used to break these barriers.
Education and Expense: The Barriers to Mass Spectrometry in Clinical Laboratories?
Here we examine the perceived barriers to mass spec in clinical laboratories and explore the possible drivers behind the recent shift in uptake of the technology in clinical settings.
Removing 62 Barriers to Pig–to–Human Organ Transplant in One Fell Swoop
The largest number of simultaneous gene edits ever accomplished in the genome could help bridge the gap between organ transplant scarcity and the countless patients who need them.
Fruit Fly Pheromone Flags Great Real Estate for Starting a Family
Finding could aid efforts to control mosquito-borne diseases like malaria by manipulating odorants
Gene Editing Could Enable Pig-To-Human Organ Transplant
The largest number of simultaneous gene edits ever accomplished in the genome could help bridge the gap between organ transplant scarcity and the countless patients who need them.
Antioxidants Cause Malignant Melanoma to Metastasize Faster
Fresh research at Sahlgrenska Academy has found that antioxidants can double the rate of melanoma metastasis in mice.
New Therapy Reduces Symptoms of Inherited Enzyme Deficiency
A phase three clinical trial of a new enzyme replacement medication, sebelipase alfa, showed a reduction in multiple disease-related symptoms in children and adults with lysosomal acid lipase deficiency, an inherited enzyme deficiency that can result in scarring of the liver and high cholesterol.
Biomarker Predicting Transplant Complications May be Key to Treating Them
A protein that can be used to predict if a stem cell transplant patient will suffer severe complications may also be the key to preventing those complications, an international research team based at the Indiana University School of Medicine reported Wednesday.
Potential New Diagnosis and Therapy for Breast Cancer
Scientists at the University of York, using clinical specimens from charity Breast Cancer Now’s Tissue Bank, have conducted new research into a specific sodium channel that indicates the presence of cancer cells and affects tumour growth rates.
First Results Describing Sick Sea Star Immune Response
Though millions of sea stars along the West Coast have perished in the past several years from an apparent wasting disease, scientists still don’t know why.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,700+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos