Neuroscience News

Findings Validate Cancer Metabolism as an Approach to Identify New Ways to Treat Cancer -
Opens Potential for New Class of Cancer Drugs Targeting Metabolic Enzymes

Cambridge, MA

Agios Pharmaceuticals today announced that its scientists have established, for the first time, that the mutated IDH1 gene has a novel enzyme activity consistent with a cancer-causing gene, or oncogene. This breakthrough discovery shows that the mutated form of IDH1 produces a metabolite, 2-hydroxyglutarate (2HG), which may contribute to the formation and malignant progression of gliomas, the most common type of brain cancers. This discovery appears to reverse the previously held belief that IDH1 was non functional for cancer-causing activity. It is also one of the first reported instances where a metabolic enzyme such as IDH1 is shown to play a role in cancer formation, in this case through altered metabolic activity.

This finding creates opportunities for therapeutic intervention in brain cancer and other cancers where IDH1 mutations are present using new drugs that can target the IDH1 metabolic pathway. The Agios research also identified an exciting new biomarker, 2HG, that could be used to develop an important diagnostic. The research was published on November 22 by the journal Nature, in a paper entitled “Cancer-associated IDH1 mutations produce 2-hydroxyglutarate (2HG)”. [1]

“This groundbreaking work is profound for the field,” said Professor Lew Cantley, Ph.D., Director of the Cancer Center at the Beth Israel Deaconess Medical Center, a founder of Agios and a supporting author. “The team at Agios has demonstrated that what was previously considered an inactive enzyme is in reality an active oncogene and a potential therapeutic target. This has fundamentally changed our understanding of the field. Additionally, there is an easily measured metabolic biomarker, 2HG, that will help in the diagnosis and treatment of any related therapeutics that arise from this work.”

Agios scientists uncovered the function of the IDH1 mutation by employing novel techniques in a new area of cancer biology called cancer metabolism, which focuses on studying profound changes in metabolic activity in cancer cells. Through a mix of large-scale profiling of hundreds of cellular metabolites, x-ray crystallography, and innovative enzymology, the Agios team demonstrated that a single amino-acid substitution in the IDH1 active site allows the enzyme to acquire an entirely new activity to produce the metabolite 2HG. Analysis of tumor samples of brain cancer patients with the IDH1 mutation revealed up to hundred-fold elevations in concentrations of 2HG, a metabolite that has been previously linked to the formation of brain cancer.

“Agios’ founding principles included the belief that targeting important metabolic pathways of cancers could make a fundamental difference in the treatment of the disease. Our IDH1 discovery is a great example of the power of the team and of our approach in targeting cancer metabolic pathways. In just four months, scientists at Agios unraveled very complex biology to advance a new understanding of gliomas and the role of IDH1 and corresponding biomarkers,” said David Schenkein, M.D., Chief Executive Officer, Agios. “We are able to do this by utilizing a unique approach of integrating deep biology and leveraging our proprietary platform for cancer metabolism research.

“We are looking forward to developing potential therapeutics specifically targeting IDH1 for patients with these devastating diseases, and to leveraging our unique cross functional approach to cancer metabolism research in order to discover insights into other targets and pathways,” added Schenkein.

About the metabolic enzyme IDH1 and its role in cancer
Recent research has linked mutations in the metabolic enzyme IDH1 to glioma and other cancers. [2] Approximately 70 percent of gliomas are known to have the IDH1 mutation. Recently, the IDH1 mutation was also shown to be present in a significant percentage of patients with Acute Myeloid Leukemia, another devastating disease.

The insight from this new research at Agios is the first to reveal the function of the mutated IDH1 gene and provides critical insight into the mechanism by which this mutation leads to the development of brain cancer. Reports to date about the role of IDH1 have suggested that the gene functions as a tumor suppressor that, when mutationally inactivated, may contribute to brain tumor growth. The most recent research from Agios scientists published in Nature [1] suggests that it is activation of a metabolic pathway – rather than inactivation of a tumor suppression function – that is the likely process for oncogene function of IDH1.

About Gliomas
A glioma is a type of cancer that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain, but gliomas can also affect the spinal cord or any other part of the CNS, such as the optic nerves. High grade gliomas currently cannot be cured and the prognosis for patients is generally poor; of the 20,000 Americans affected each year, more than half die within eighteen months of diagnosis. Gliomas are the most common type of brain cancer and approximately 70 percent of lower grade gliomas are known to have the IDH1 gene mutation.

About Cancer Metabolism
Cancer metabolism is a new and exciting field of biology that provides a novel approach to treating cancer. Cancer cell metabolism is marked by profound changes in nutrient requirements and usage to ensure cell proliferation and survival. Research in the field has demonstrated that cancer cells become addicted to certain fuel sources and metabolic pathways. In cancer, this metabolic reprogramming is coordinated with proliferative signaling and regulated by the same oncogenes and tumor suppressor genes to ensure efficient proliferation. Glycolysis (sugar metabolism), fatty acid metabolism and autophagy (self metabolism) are three pathways shown to play a critical role in cancer metabolism. Identifying and disrupting certain enzymes in these, and perhaps other, metabolic pathways provides a powerful intervention point for discovery and development of cancer therapeutics.

About Agios Pharmaceuticals
Agios Pharmaceuticals is the first biopharmaceutical company dedicated to the discovery and development of novel therapeutics in the emerging field of cancer metabolism. To support and drive these efforts, Agios is building a robust platform integrating metabolomics, genetics, biochemistry and microscopy to enable biomarker and target identification. Agios’ capabilities to interrogate differential cellular metabolism of diseased cells relative to normal cells will also be applicable to other therapeutics areas including autoimmune, inflammatory and neurological diseases. To date, Agios has put in place a world-class scientific team of more than 60 people, built a fully integrated cell metabolism platform within the largest research laboratory dedicated to cancer metabolism and created an emerging product development pipeline of novel cancer therapeutics. The Company’s founders represent the core thought leaders in the field of cancer metabolism, responsible for key advances, insights and discoveries in the field. Agios Pharmaceuticals is located in Cambridge, Massachusetts. For more information, please visit the company’s website at www.agios.com.

[1] Dang et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009;In press. DOI: 10.1038/nature08617

[2] Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807-12 (2008); Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 360, 765-73 (2009).

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Kathryn Morris

ST. PAUL, Minn. – New guidelines from the American Academy of Neurology identify the most effective treatments for amyotrophic lateral sclerosis (ALS), often called Lou Gehrig’s disease. The guidelines are published in the October 13, 2009, issue of Neurology®, the medical journal of the American Academy of Neurology.

“While we are waiting for a cure, people need to know that a lot can be done to make life easier and longer for people with ALS,” said lead guidelines author Robert G. Miller, MD, with the Department of Neurology at California Pacific Medical Center in San Francisco and Fellow of the American Academy of Neurology.

ALS is a rapidly progressive and fatal neurologic disease that attacks the nerve cells that control voluntary muscles. Eventually people with ALS are not able to stand or walk, or use their hands and arms, and they have difficulty breathing and swallowing. Most people with ALS die within three to five years from the onset of symptoms. However, about 10 percent survive for 10 or more years.

According to the guidelines, the drug riluzole should be offered to people with ALS to slow the rate at which the disease progresses. Riluzole is the only drug approved by the U.S. Food and Drug Administration to treat ALS and has a modest effect on prolonging survival.

The guidelines also state that life expectancy will likely increase and quality of life may increase for people with ALS who use an assisted-breathing device. Longer life expectancy is also likely for people with ALS who use a feeding tube known as a PEG tube, since nutrition plays a critical role in prolonging survival. The guidelines also recommend doctors consider offering their patients botulinum toxin B to treat sialorrhea, also known as drooling, if oral medications do not help. Moreover, doctors should consider screening their patients for behavioral or thinking problems because studies show many people with ALS have these problems. Such problems might affect some patients’ willingness to accept suggested treatments.

“Important treatments available for people with ALS are often not suggested by doctors and not used by patients,” said Miller. “It’s important that people with ALS know that more treatments are now available to ease the burden of the disease and that they should see neurologists who are aware of these new guidelines and follow them.”

In addition, the guidelines recommend people with ALS enroll early in a specialized multidisciplinary ALS clinic to optimize care. “Attending a multidisciplinary clinic will likely increase survival and access to treatments, and may improve quality of life,” said Miller.

The cause of ALS is not known, and it’s not yet known why ALS strikes some people and not others.

About The American Academy of Neurology 

The American Academy of Neurology, an association of more than 21,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as epilepsy, dystonia, migraine, Huntington’s disease and dementia.

Discovery could lead to treatments for learning and memory deficits, particularly Noonan’s syndrome

Cold Spring Harbor, N.Y. – As most good students realize, repeated studying produces good memory. Those who study a lot realize, further, that what they learn tends to be preserved longer in memory if they space out learning sessions between rest intervals. Neuroscientists at Cold Spring Harbor Laboratory (CSHL) have now discovered how this so-called “spacing effect” is controlled in the brain at the level of individual molecules.

Led by Professor Yi Zhong, Ph.D., the CSHL team has found that a protein called SHP-2 phosphatase controls the spacing effect by determining how long resting intervals between learning sessions need to last so that long-lasting memories can form. The study, carried out in a fruit fly model, will appear online in the journal Cell on October 2.

“Although there are many theories that explain the spacing effect at the psychological level and hundreds of studies that back them up, there has not been any understanding of this phenomenon at the neurobiological level,” says Zhong. “We have shown for the first time that the spacing effect has a genetic and molecular basis.”

Not only that, but Zhong’s team has also found that the duration of the resting intervals can be manipulated for achieving better memory by genetically altering SHP-2 phosphatase. “This ability to exploit the spacing effect’s molecular control to enhance memory could be useful in a wide range of settings such as education, advertising, and most importantly, in treating learning and memory disorders,” says Zhong.

How excess protein activity impedes long-term memory

Zhong has long been interested in genes that when mutated trigger learning and memory disorders such as Noonan’s syndrome, a genetically inherited disease with an incidence rate of 1 in 1000 to 1 in 2000 people. More than 50% of Noonan’s patients have mutations in a gene called PTP11, which encodes the SHP-2 phosphatase protein. In contrast to many disease-related mutations that shut off protein production or impair protein activity, these PTP11 mutations do the opposite – they boost the activity levels of SHP-2 phosphatase.

To understand how this change impedes long-term memory, Zhong’s team engineered these mutations into a gene in fruit flies called corkscrew that is the functional equivalent of PTP11 in humans. The mutant flies were taught to avoid certain odors via a training regimen of repeated learning sessions broken up by resting intervals lasting 15 minutes. But this training regimen, which induces long-term memory in normal flies, failed to work in the mutants because the increased activity of SHP-2 phosphatase disturbed the spacing effect.

Zhong’s team found that normally, as each learning period ends, SHP-2 phosphatase activity inside stimulated neurons triggers a wave of biochemical signals, which have to peak and decay before the next learning session can begin. “The repeated formation and decay of the biochemical signal during each rest interval induces long-term memory,” explains Zhong.

In normal flies, these signal waves took 15 minutes to peak and decay. In the mutants that had excess protein activity, however, the signaling wave took 40 minutes to decay, the team discovered. “A training regimen that includes only 15 minute rest intervals therefore fails in the mutants because increased SHP-2 phosphatase activity somehow causes the waves of signals to fall out of sync,” explains Zhong. “So it’s crucial that the period of rest should last as long as it takes for a signal wave to form and reset.”

In contrast to increased SHP-2 phosphatase activity, which lengthened the resting interval to 40 minutes, the team found that increased production of the protein with normal activity could shorten the duration of the resting interval to 2.5 minutes. “These findings suggest that SHP-2 phosphatase acts as a molecular timer that determines how long resting intervals should last,” says Zhong.

Reversing memory deficits

Zhong’s team has succeeded in reversing memory deficits in mutant flies in two ways. Either reducing the activity of mutated SHP-2 phosphatase to normal levels with drugs or simply altering training regimens to include 40-minute rest intervals instead of the normal 15 minutes both established long-term memory in the mutants.

“Our results suggest that longer resting intervals for Noonan’s patients might reverse their memory deficits,” says Zhong. His team is currently collaborating with clinicians to determine whether this intervention, which worked in flies, will also work in people afflicted with Noonan’s.

—

“Spacing Effect: SHP-2 Phosphatase Regulates Resting Intervals Between Learning Trials in Long-Term Memory Induction” appears in Cell on October 2nd. The full citation is: Mario R. Pagani, Kimihiko Oishi, Bruce D. Gelb and Yi Zhong.

Cold Spring Harbor Laboratory is a private, nonprofit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding of and ability to diagnose and treat cancers, neurological diseases and other causes of human suffering.

Contact:

Contact: Hema Bashyam
bashyam@cshl.edu
516-367-6822
Cold Spring Harbor Laboratory

New research in the FASEB Journal demonstrates role of IL-6 on sleep-related consolidation of specific types of memories, particularly during late night REM sleep cycles.

Good news for procrastinating students: a nasal spray developed by a team of German scientists promises to give late night cram sessions a major boost, if a good night’s sleep follows. In a research report featured as the cover story of the October 2009 print issue of The FASEB Journal, (http://www.fasebj.org) these scientists show that a molecule from the body’s immune system (interleukin-6) when administered through the nose helps the brain retain emotional and procedural memories during REM sleep.

“Sleep to remember, a dream or reality?” said Lisa Marshall, co-author of the study, from the Department of Neuroendocrinology at the University of Lubeck in Germany. “Here, we provide the first evidence that the immunoregulatory signal interleukin-6 plays a beneficial role in sleep-dependent formation of long-term memory in humans.”

To make this discovery, Marshall and colleagues had 17 healthy young men spend two nights in the laboratory. On each night after reading either an emotional or neutral short story, they sprayed a fluid into their nostrils which contained either interleukin-6 or a placebo fluid. The subsequent sleep and brain electric activity was monitored throughout the night. The next morning subjects wrote down as many words as they could remember from each of the two stories. Those who received the dose of IL-6 could remember more words.

“If a nasal spray can improve memory, perhaps we’re on our way to giving some folks a whiff of common sense, such as accepting the realities of evolution,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “This is exciting piece of interdisciplinary science, since IL-6 had previously been considered a by-product of inflammation, not an agent that affects cognition.”

 Details: Christian Benedict, Jürgen Scheller, Stefan Rose-John, Jan Born, and Lisa Marshall. Enhancing influence of intranasal interleukin-6 on slow-wave activity and memory consolidation during sleep. FASEB J. 2009 23: 3629-3636. DOI: 10.1096/fj.08-122853

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