A team of investigators has uncovered a potentially promising strategy to target brain tumours -- isocitrate dehydrogenase (IDH) genes, which are the most common brain tumours diagnosed in younger adults aged 18 to 45 years.
Led by investigators at Massachusetts General Hospital, the finding of their study are published in Cancer Discovery, a journal of the American Association for Cancer Research.
Prior work by the group, led by Mass General's Daniel Cahill, MD, PhD, Hiroaki Wakimoto, MD, PhD, and Julie Miller, MD, PhD, revealed that IDH mutant gliomas have a metabolic weakness making them especially susceptible to treatments that lower NAD+ levels, a ubiquitous and vital metabolic molecule commonly thought of as the "currency of metabolism" in cells.
Also, previous work by other researchers found that chemotherapy activates an enzyme that stimulates NAD+ molecules to join together to make poly (ADP-ribose), or PAR, a key DNA damage signal.
This PAR signal is a known susceptibility in IDH mutant gliomas.
Researchers also discovered that activation of the enzyme by chemotherapy causes available NAD+ to be critically depleted for the production of PAR in IDH mutant glioma cells, but not normal cells.
These findings indicated that maintaining high PAR levels (and low NAD+ levels), in combination with chemotherapy, may uniquely target IDH mutant glioma cells.
Considering this, Hiroaki Nagashima, MD, PhD, research fellow and lead author, devised a new treatment strategy and tested it in tumour cells and animal models.
