WASHINGTON, DC: A team of researchers has discovered a promising strategy to target brain tumors, isocitrate dehydrogenase (IDH), the most common brain tumor diagnosed in young adults aged 18 to 45 years. gene.
The findings, led by researchers at Massachusetts General Hospital, appear in Cancer Discovery, a journal of the American Cancer Research Association.
A previous study by a group headed by Dr. Daniel Cahill of Mass General, Dr. Hiroaki Wakimoto, and Dr. Julie Miller, found that IDH-mutated gliomas have poor metabolism, especially for treatments that reduce NAD. It has been shown to be highly sensitive at levels that are ubiquitous and important metabolic molecules, commonly considered to be the “currency of metabolism” in cells.
Earlier studies by other researchers have also found that chemotherapy stimulates NAD molecules to activate poly(ADP-ribose), or PAR, an enzyme that produces major DNA damage signals. This PAR signal is a known susceptibility in IDH mutant gliomas.
The researchers also found that the activation of the enzyme by chemotherapy greatly depleted the NADs available for PAR production in IDH-mutant glioma cells but not in normal cells.
These findings indicate that maintaining high PAR levels (and low NAD levels) in combination with chemotherapy may uniquely target IDH mutant glioma cells. With this in mind, researcher and lead author Hiroaki Nagashima, MD, devised a new therapeutic strategy and tested it on tumor cells and animal models.
“The greatest efficacy comes from two drugs, temozolomide, the most commonly used chemotherapy to treat patients with IDH mutant gliomas, and a drug that inhibits PAR degradation known as PAR glycohydrolase inhibitors. It was achieved by combining the two.
Dr. Wakimoto, Associate Professor of Neurosurgery, Harvard Medical School, said: “We have shown for the first time that PAR glycohydrolase inhibitors can be used to enhance the efficacy of chemotherapy in tumors with reduced NAD pathway metabolism.
Dr. Miller, Neurology-Incologist at Mass General, a neurology instructor who treats patients with IDH-mutated glioma, said PAR glycohydrolase inhibitors are an emerging class of drugs.
“The long-term importance is that, based on our findings, it can be tested in individuals with IDH-mutant glioma with the goal of hopefully improving the outcomes of these patients,” she said.
This article was published from a wire transfer feed with no changes to the text.
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