Gliomas with mutations in a gene called the isocitrate dehydrogenase (IDH) gene are the most common brain tumors diagnosed in young adults aged 18 to 45 years. Patients can benefit from aggressive surgery, radiation therapy, and chemotherapy, but these treatments are often not curative.
Now a team headed by Massachusetts General Hospital investigators has identified potentially promising strategies to target these tumors and improve their treatment. The survey results are Cancer discovery, Journal of the American Cancer Research Association.
Previous work by a group led by mass general Daniel Cahill, MD, PhD, Hiroaki Wakimoto, MD, PhD,and Julie Miller, MD, PhD, IDH-mutated gliomas have metabolic weaknesses and are particularly sensitive to treatments that lower the levels of NAD +, a ubiquitous and important metabolic molecule commonly thought to be the “metabolic currency” in cells Was revealed to be high.
Earlier studies by other researchers have also shown that chemotherapy stimulates NAD + molecules to activate enzymes and bind poly(ADP-ribose), or PAR, to become the major DNA damage signal. discovered. This PAR signal is a known susceptibility in IDH mutant gliomas. The researchers also found that activation of the enzyme by chemotherapy led to a significant depletion of available NAD + for the production of PAR 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, Hiroaki Nagashima, MD, PhD, A researcher and lead author, devised a new therapeutic strategy and tested it on tumor cells and animal models.
“We found that the greatest effect was achieved by combining two drugs: temozolomide, the most commonly used chemotherapy to treat patients with IDH-mutated glioma, and PAR glyco We use drugs that block PAR degradation, known as hydrolase inhibitors,” said Cahill. Mass General Neurosurgical Oncologist and Associate Professor of Neurosurgery at Harvard Medical School.
Dr. Wakimoto, Associate Professor of Neurosurgery at Harvard Medical School, said: “We show for the first time that PAR glycohydrolase inhibitors can be used to enhance the efficacy of chemotherapy for tumors with hypometabolism in the NAD + pathway.
Dr. Miller, a neurooncologist at Mass General, a neurology instructor who treats patients with IDH mutant gliomas, said PAR glycohydrolase inhibitors are an emerging drug class. “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.
Reference: Hiroaki Nagashima et al. (2020) Poly(ADP-ribose) glycohydrolase inhibition sequesters NID + and enhances metabolic lethality of alkylating chemotherapy in IDH mutant tumor cells. Cancer Discov. DOI: 10.1158 / 2159-8290.CD-20-0226
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