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Reversing effects of altered enzyme may fight brain tumor growth
April 14, 2009An international team of scientists from the Moores Cancer Center at the University of California, San Diego, the University of North Carolina and several institutions in China have explained how a gene alteration can lead to the development of a type of brain cancer, and they have identified a compound that could staunch the cancer's growth.
The researchers, led by Kun-Liang Guan, PhD, professor of pharmacology at the UC San Diego School of Medicine, have shown that when a mutated enzyme fails to do its job, the development of tumor-feeding blood vessels increases, allowing more nutrients and oxygen to fuel cancer growth. They have also shown in the laboratory that they could reverse the mutant enzyme's effects, effectively blocking this process, called angiogenesis, and provide a potential future treatment strategy against some types of brain tumors. They reported their findings in the current issue of the journal Science.
According to Guan, researchers have known that a mutation in the gene encoding the enzyme, isocitrate dehydrogenase (IDH1), contributed to certain brain tumors called low grade gliomas and secondary glioblastomas, but no one understood how. Guan, Yue Xiong, PhD, at the University of North Carolina and their co-investigators have now shown that this is because alterations in a specific gene, IDH1, impairs the body's ability to keep a tumor growth-promoting protein, HIF-1 alpha, in check.
The IDH1 enzyme works to produce a compound called alpha-KG, which is required for HIF-1 breakdown. Without that control, HIF-1 can run amok, promoting angiogenesis and tumor growth. The team was able to reverse this HIF-1 alpha effect by adding a modified form of alpha-KG to brain tumor cells in culture.
"This suggests a direction to exploit cell permeable alpha-KG for potential treatment of brain cancer patients with an IDH1 mutation," Guan said.
He added that IDH1 appears to function as a tumor suppressor gene that when altered - and turned off - can contribute to tumor formation through the HIF-1 pathway. But Guan noted, "IDH1 is not your usual suspect as a cancer gene."
He explained that the alteration in IDH1 is a substitution of an amino acid in one copy of the gene without losing the other normal copy (every gene in normal human cells has two copies), which is different from most tumor suppressor genes. Most either have genetic material that is deleted or truncated - not a single amino acid substitution.
Guan, Xiong and their group are hopeful about their findings. Understanding mechanisms behind the development of such brain tumors is critical to clinical advances, Guan said. "Because of their ability to reverse HIF-1 levels, drugs mimicking alpha-KG may be worth exploring as possible therapies for these types of gliomas."
University of California - San Diego
The IDH1 enzyme works to produce a compound called alpha-KG, which is required for HIF-1 breakdown. Without that control, HIF-1 can run amok, promoting angiogenesis and tumor growth. The team was able to reverse this HIF-1 alpha effect by adding a modified form of alpha-KG to brain tumor cells in culture.
"This suggests a direction to exploit cell permeable alpha-KG for potential treatment of brain cancer patients with an IDH1 mutation," Guan said.
He added that IDH1 appears to function as a tumor suppressor gene that when altered - and turned off - can contribute to tumor formation through the HIF-1 pathway. But Guan noted, "IDH1 is not your usual suspect as a cancer gene."
He explained that the alteration in IDH1 is a substitution of an amino acid in one copy of the gene without losing the other normal copy (every gene in normal human cells has two copies), which is different from most tumor suppressor genes. Most either have genetic material that is deleted or truncated - not a single amino acid substitution.
Guan, Xiong and their group are hopeful about their findings. Understanding mechanisms behind the development of such brain tumors is critical to clinical advances, Guan said. "Because of their ability to reverse HIF-1 levels, drugs mimicking alpha-KG may be worth exploring as possible therapies for these types of gliomas."
University of California - San Diego
Brain Tumor Current Events and Brain Tumor News RSSChildhood cancer survivors less likely to marry, Yale researchers find
Adult survivors of childhood cancer are 20 to 25 percent more likely to never marry compared with siblings and the general population, Yale School of Medicine researchers report in a new study published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.
Brain tumors in childhood leave a lasting mark on cognition, life status
Brain tumors in childhood cast a long shadow on survivors. The first study of the lasting impact of these tumors -- the most common solid malignancies in childhood -- shows that survivors have ongoing cognitive problems.
Angiochem crosses BBB, shows safety, efficacy in phase 1/2 brain cancer studies
Angiochem, Inc. a clinical-stage biotechnology company developing drugs that are uniquely capable of crossing the blood-brain barrier to treat brain diseases, announced today that its lead drug candidate, ANG1005, has demonstrated a favorable safety and efficacy profile in more than 100 patients with brain cancer from two separate Phase 1 /2 clinical studies in patients with progressive gliomas, including recurrent glioblastoma, and in patients with progressive brain metastases.
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.
Weizmann Institute Scientists Discover A New Protein Partnership That Leads to Pediatric Tumor Regression
Why are some pediatric cancers able to spontaneously regress? Prof. Michael Fainzilber and his team of the Weizmann Institute's Biological Chemistry Department seem to have unexpectedly found part of the answer.
Why don't brain tumors respond to medication?
Malignant brain tumors often fail to respond to promising new medication. Researchers in Heidelberg have discovered a mechanism and a tumor marker for the development of this resistance.
NIH researchers identify key factor that stimulates brain cancer cells to spread
Researchers funded by the National Institutes of Health have found that the activity of a protein in brain cells helps stimulate the spread of an aggressive brain cancer called glioblastoma multiforme (GBM).
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