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New therapeutic target identified in inherited brain tumor disorder
November 02, 2005Researchers studying a mouse model of neurofibromatosis 1 (NF1), a genetic condition that causes childhood brain tumors, have found their second new drug target in a year, a protein called methionine aminopeptidase-2 (MetAP2).
An established drug, fumagillin, is already known to suppress the activity of MetAP2. Researchers at Washington University School of Medicine in St. Louis showed that fumagillin significantly slowed the rapid proliferation of cultured mouse brain cells that resulted from the loss of Nf1, the gene that causes neurofibromatosis 1. Evaluation of the ability of this class of drugs to control brain tumor growth in small animal models is planned.
"This agent and others like it have already been in clinical trials as treatments for other tumors, so if we find that fumagillin inhibits brain tumor growth in preclinical studies, it will be a much smaller leap to using these compounds in patients with NF1," says senior investigator David H. Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology at Washington University School of Medicine in St. Louis and co-director of the neuro-oncology program at the Siteman Cancer Center.
Neurofibromatosis 1 affects more than 100,000 people in the United States and is one of the most common tumor predisposition syndromes. Gutmann and his colleagues discovered that abnormally high levels of MetAP2 may be a distinguishing characteristic of brain tumors in patients with NF1. Analyses of other similar brain tumors did not reveal the high MetAP2 levels characteristic of tumors caused by NF1.
To identify MetAP2, Gutmann collaborated with Jason D. Weber, Ph.D., assistant professor of medicine and of cellular biology and anatomy at the Washington University Neurofibromatosis Center. The center facilitates multidisciplinary neurofibromatosis research and is dedicated to developing better treatments to improve the lives of patients affected with neurofibromatosis.
Researchers in Gutmann's and Weber's laboratories took samples of cerebrospinal fluid from wild-type mice and a genetically engineered mouse model of NF1. Using a technique called proteomic analysis, they looked at the number of times copies of any given protein were found in the fluid. The goal was to identify proteins whose levels were different in the spinal fluid of the mouse model compared to normal mice.
Gutmann and Weber previously used the genetically engineered mice for a proteomic analysis of astrocytes, the brain cells that often become cancerous in patients with NF1. That led to the finding that proteins in the mammalian target of rapamycin pathway (mTOR) are overactivated, suggesting that mTOR may be a promising target for future chemotherapy for NF1-associated brain tumors.
The new study's results suggest that MetAP2 may be directly regulated by neurofibromin, the protein produced by the Nf1 gene.
Like the mTOR pathway proteins, MetAP2 is normally active in processes that regulate the production of proteins from RNA. Gutmann and Weber plan additional studies to determine how increased MetAP2 expression enables astrocyte growth and brain tumor development.
"The availability of a mouse model of NF1-associated brain tumors allows us to conduct experiments that we could never perform in humans that have already broadened our understanding of the function of the Nf1 gene," Gutmann says. "It's highly likely that these new insights will lead to new treatments for NF1 patients."
Dasgupta B, Yi Y, Hegedus B, Weber JD, Gutmann DH. Cerebrospinal fluid proteomic analysis reveals dysregulation of methionine aminopeptidase-2 expression in human and mouse neurofibromatosis 1-associated glioma. Cancer Research, November 1, 2005.
Funding from the U.S. Department of Defense supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Washington University in St. Louis
Neurofibromatosis 1 affects more than 100,000 people in the United States and is one of the most common tumor predisposition syndromes. Gutmann and his colleagues discovered that abnormally high levels of MetAP2 may be a distinguishing characteristic of brain tumors in patients with NF1. Analyses of other similar brain tumors did not reveal the high MetAP2 levels characteristic of tumors caused by NF1.
To identify MetAP2, Gutmann collaborated with Jason D. Weber, Ph.D., assistant professor of medicine and of cellular biology and anatomy at the Washington University Neurofibromatosis Center. The center facilitates multidisciplinary neurofibromatosis research and is dedicated to developing better treatments to improve the lives of patients affected with neurofibromatosis.
Researchers in Gutmann's and Weber's laboratories took samples of cerebrospinal fluid from wild-type mice and a genetically engineered mouse model of NF1. Using a technique called proteomic analysis, they looked at the number of times copies of any given protein were found in the fluid. The goal was to identify proteins whose levels were different in the spinal fluid of the mouse model compared to normal mice.
Gutmann and Weber previously used the genetically engineered mice for a proteomic analysis of astrocytes, the brain cells that often become cancerous in patients with NF1. That led to the finding that proteins in the mammalian target of rapamycin pathway (mTOR) are overactivated, suggesting that mTOR may be a promising target for future chemotherapy for NF1-associated brain tumors.
The new study's results suggest that MetAP2 may be directly regulated by neurofibromin, the protein produced by the Nf1 gene.
Like the mTOR pathway proteins, MetAP2 is normally active in processes that regulate the production of proteins from RNA. Gutmann and Weber plan additional studies to determine how increased MetAP2 expression enables astrocyte growth and brain tumor development.
"The availability of a mouse model of NF1-associated brain tumors allows us to conduct experiments that we could never perform in humans that have already broadened our understanding of the function of the Nf1 gene," Gutmann says. "It's highly likely that these new insights will lead to new treatments for NF1 patients."
Dasgupta B, Yi Y, Hegedus B, Weber JD, Gutmann DH. Cerebrospinal fluid proteomic analysis reveals dysregulation of methionine aminopeptidase-2 expression in human and mouse neurofibromatosis 1-associated glioma. Cancer Research, November 1, 2005.
Funding from the U.S. Department of Defense supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Washington University in St. Louis
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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.
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Angiochem crosses BBB, shows safety, efficacy in phase 1/2 brain cancer studies
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Researchers report benefits of new standard treatment study for rare pediatric brain cancer
A team of researchers led by The University of Texas M. D. Anderson Cancer Center unveiled results today from the largest-ever collaborative study addressing the treatment of a rare pediatric brain tumor.
Unequal access: Hispanic children rarely get top-notch care for brain tumors
Hispanic children diagnosed with brain tumors get high-quality treatment at hospitals that specialize in neurosurgery far less often than other children with the same condition, potentially compromising their immediate prognosis and long-term survival, according to research from Johns Hopkins published in October's Pediatrics.
tudy: The new buzz on detecting tinnitus
It's a ringing, a buzzing, a hissing or a clicking - and the patient is the only one who can hear it. Complicating matters, physicians can rarely pinpoint the source of tinnitus, a chronic ringing of the head or ears that can be as quiet as a whisper or as loud as a jackhammer.
New Approach for the Treatment of Malignant Brain Tumors
Initial chemotherapy alone after surgery is just as successful as initial radiation therapy for patients from whom a very malignant brain tumor (anaplastic glioma) was removed. With this treatment, the patients survive on average > 30 months without a recurrence.
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