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Reversing effects of altered enzyme may fight brain tumor growth
Date:4/14/2009

An 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 suppre
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Contact: Steve Benowitz
sbenowitz@ucsd.edu
619-543-6163
University of California - San Diego
Source:Eurekalert

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