New Blue Print for Treating a Deadly Brain Tumor

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NIH-funded researchers showed how gliomas may be treated with radiation and drugs that block DNA repair. Castro lab, Michigan Medicine, Ann Arbor

NIH-funded, preclinical study suggests a common form of brain cancer may be treated with combination radio- and chemotherapy

by National Institutes of Health News Release

In a study of mice and human brain tumors researchers at the University of the Michigan, Ann Arbor, searched for new treatments by exploring the reasons why some patients with gliomas live remarkably longer than others. The results suggested that certain patients’ tumor cells are less aggressive and much better at repairing DNA than others but are difficult to kill with radiation. The researchers then showed that combining radiation therapy with cancer drugs designed to block DNA repair may be an effective treatment strategy. The study was funded by the National Institutes of Health.

The researchers focused on low-grade gliomas that carry a disease-causing mutation in a gene called isocitrate dehydrogenase 1 (IDH1), which encodes a protein known to help cells produce energy. This mutation is found in about 50 percent of cases of primary low-grade gliomas, a common and lethal form of brain tumor. Glioma patients whose tumors have mutations in IDH1 are typically younger and live longer than those whose tumors have the normal gene.  These tumors also often have mutations in genes called TP53 (a tumor suppressor gene) and ATRX (a DNA-protein complex remodeling gene).

“Every year thousands of people are diagnosed with brain cancer and have little hope for long-term survival,” said Maria G. Castro, Ph.D., professor of neurosurgery at Michigan Medicine and a senior author of the paper published in Science Translational Medicine. “Our team’s mission is to find life-saving treatments for these patients. The results from this study could be a blueprint for extending, if not saving, the lives of many patients.”

The researchers recreated the patients’ tumors by genetically engineering mice to grow brain cancer cells that have the disease-causing mutations in IDH1 along with mutations in TP53 and ATRX. Like the patients, these mice lived longer than control mice whose tumors were programmed to have normal IDH1 while still harboring the mutations in TP53 and ATRX.

When the research team examined the tumors, they found that the IDH1 mutation made the glioma cells less aggressive. The cells divided at a lower rate than the controls and were much less likely   to trigger tumor growth when implanted into mouse brains.

They also discovered that the IDH1 mutation, in the presence of mutations in TP53 and ATRX, made the tumors resistant to ionizing radiation, a treatment that kills cells often by damaging DNA. For instance, radiation exposure extended the lives of mice that were implanted with control tumors but had no effect on mice implanted with IDH1 mutant cells.

Further experiments provided a possible explanation for this resistance. The results suggested the disease-causing mutation changed the activity of IDH1 which, in turn, triggered a cascade of chemical reactions that modified the cancer cells’ genes in a way that increased the manufacture of proteins known to repair damaged DNA.

“Our results demonstrate that the metabolic changes caused by the IDH1 mutation reprograms brain cancer cells,” said Dr. Castro.

These results led the researchers to formulate and test a new combination therapy. They found that they could extend the lives of mice with mutant IDH1 tumors by exposing them to radiation while also injecting them with anti-cancer drugs designed to block DNA repair. In contrast, treating these mice with either radiation or one of the drugs alone had no effect. Several of the findings seen in mice were also seen in human gliomas grown in petri dishes.

“These findings have the potential to impact many younger glioma patients with low grade tumors by either ‘curing’ them or extending their lives,” said Jane Fountain, Ph.D., program director, NIH’s National Institute of Neurological Disorders and Stroke. “The preclinical model Dr Castro’s team developed will be extremely valuable to cancer researchers. It closely mirrors the human disease.”

Dr. Castro’s team has started planning a Phase 1 clinical trial which will test the safety and efficacy of the combination therapy strategy outlined in this study.

This study was supported by grants from the NIH (NS094804, NS105556, NS076991, NS096756, NS099427, NS103500, NS106887, EB022563, CA224160, CA009676, CA151022, DK097153).

NINDS (http://www.ninds.nih.gov) is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH’s efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI’s Contact Center, the Cancer Information Service, at 1-800-4-CANCER (1-800-422-6237).

About the National Institute of Biomedical Imaging and Bioengineering: NIBIB’s mission is to improve health by leading the development and accelerating the application of biomedical technologies. The Institute is committed to integrating the physical and engineering sciences with the life sciences to advance basic research and medical care. NIBIB supports emerging technology research and development within its internal laboratories and through grants, collaborations, and training. More information is available at the NIBIB website: http://www.nibib.nih.gov.

About the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): The NIDDK, part of the NIH, conducts and supports basic and clinical research and research training on some of the most common, severe, and disabling conditions affecting Americans. The Institute’s research interests include diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic, and hematologic diseases. For more information, visit www.niddk.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Article

Nunez, F.J..; “IDH-R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response,” February 13, 2019, Science Translational Medicine; DOI: 10.1126/scitranslmed.aaq1427

Biography
Carol graduated from Riverside White Cross School of Nursing in Columbus, Ohio and received her diploma as a registered nurse. She attended Bowling Green State University where she received a Bachelor of Arts Degree in History and Literature. She attended the University of Toledo, College of Nursing, and received a Master’s of Nursing Science Degree as an Educator.

She has traveled extensively, is a photographer, and writes on medical issues. Carol has three children RJ, Katherine, and Stephen – one daughter-in-law; Katie – two granddaughters; Isabella Marianna and Zoe Olivia – and one grandson, Alexander Paul. She also shares her life with husband Gordon Duff, many cats, and two rescue pups.

Carol’s Archives 2009-2013
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3 COMMENTS

  1. I have a life long friend in California who will be 81 next month. About 5 years ago he was diagnosed with a benign brain tumor. Doctors at Kaiser removed it. When I talk to him by phone he is very lucid and remembers many details. But he has been confined to a nursing home ever since. And this was just a “benign” tumor.
    An article in the NY Times a few years ago indicated the cancer generals have spent between $100 billion and $1 trillion on cancer research since the beginning of the war on cancer in 1971. The cancer death rates remain about unchanged. Obviously they do not know what they are doing and don’t want to know what they are doing because everybody treating this disease is making too much easy money now. About the same time period that the genius in Germany Otto H. Warburg, M.D., Ph.D. completed his proof of the prime cause of cancer as oxygen deficiency to cells in the 1955-1965 period, along come the DNA stuff of Watson and Crick. The non scientists quickly jumped on that and assumed it would solve the cancer problem without proof and dismissed Warburg’s great discoveries out of hand.
    Well, they were wrong and have cause and effect mixed up a common problem in science. This is why they have gotten nowhere and will get nowhere until they acknowledge they are wrong and Warburg was right. Everyone in the corrupt NCI, NIH must be fired and prosecuted for fraud and crimes against humanity. This is a national disgrace. Warburg was considered the greatest biochemist of the 20th century. He was awarded the 1931 solo Nobel Prize for the cell respiration work and was nominated for two others the first cancer prize in 1926 which was unfortunately awarded to Fibiger whose work was shown to be wrong, and another for different work in 1944 but denied by Hitler’s decree. Three of his pupils earned shared Nobel Prizes. He was the best of the best way above any of the bigoted non scientists in this field today. Prejudice has no place in science.

    • These non scientists also hated Warburg’s guts for remaining in Germany through Hitler’s period. Warburg used live tissue in the early experiments with rats. He invented the tissue slice technique. He also invented a special device for measuring cellular oxygen pressure called the Warburg Manometer. I believe the original is on display in a museum in Germany. Warburg died in 1970. There is a great recent book detailing the many articles by Warburg on this subject mostly in Germany journals. It is called “The Hidden Story of Cancer” by Brian Peskin, E.E. and Amid Habib, M.D., Pinnacle Press, Houston, 2006-2010. Brian holds an electrical engineering degree from MIT and got interested in health problems. This is a very readable book. He lives in Houston, Texas.
      Warburg’s papers are scattered around in many mostly German journals. Warburg published over 500 scientific papers and books in his lifetime. He was the best of the best.

    • By the way Warburg also proved that the well know causes of cancer; namely, radiation and certain chemicals, merge into this prime cause of oxygen deficiency to living cells. Your body has about 100 trillion cells. All of them must be saturated with oxygen at all times. This is a big job because there is not a blood supply, which provides this oxygen, running next to each cell in the body. The oxygen is provided by the basic physics process of diffusion. When this process is impeded, oxygen deficiency can result leading to cancer after a relatively long period of time for humans of the order of decades. There is a certain period where oxygen impaired cells can be reversed back to normal; after that period they must be excised from the body. All this and more was proved by the extensive experiments in the laboratory of Otto Warburg, M.D., Ph. D. in Germany decades ago. These experiments and facts have been criminally obstructed and ignored by the totally corrupt cancer generals of the failed war on cancer. Shame on them.

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