DNA-repairing metabolite may lead to improved cancer treatments

Researchers have discovered how a metabolite involved in repairing damaged DNA not only controls a person’s sensitivity to cancer therapies but can also protect healthy tissues from damage. The findings may lead to more effective treatments for cancer.

At the cellular level, damaged DNA that’s not properly repaired can lead to genomic instability, which, in turn, can lead to cancer and other genetic diseases. Metabolites called nucleotides, the building blocks of DNA, are involved in DNA repair, but how cell metabolism regulates that repair has not been completely understood.

Now, researchers from Michigan Medicine at the University of Michigan have found the mechanism by which a particular nucleotide metabolite, guanosine triphosphate or GTP, controls DNA repair and impacts the effectiveness of radiation and chemotherapy treatments for brain cancer.

“We learned that if you increase a cell’s GTP levels, it makes it really resistant to radiation or chemotherapy,” said Daniel Wahl, corresponding author of the study. “Lowering GTP levels, the cell becomes much more sensitive.”

It’s long been known that levels of nucleotides like GTP control how fast DNA damage is repaired, which has a direct bearing on a person’s sensitivity to cancer therapies. But, in the current study, the researchers discovered how GTP affects the DNA repair process.

“GTP impacts resistance or sensitivity to treatment not just because it’s a building block of DNA, as we previously thought,” Wahl said. “Instead of only affecting the physical structure of DNA, it also acts as a signaler. The levels of GTP turn on a signaling pathway and give cells instructions to repair damaged DNA.”

Importantly, the researchers found that GTP’s DNA-repairing effects occur in malignant and non-malignant – that is, healthy – cells. They say that their discovery that GTP acts as a signaler has important clinical implications.

“It’s a generalizable finding,” said Weihua Zhou, the study’s lead author. “In the future, we’d like to develop therapeutics that leverage the relationship between GTP and DNA damage response, both to make cancer cells more sensitive to chemotherapy and radiation and also to boost GTP levels to protect normal tissue from damage.”

The researchers are currently undertaking clinical trials using the FDA-approved drug mycophenolate mofetil (MMF) on patients with glioblastoma, a lethal form of brain cancer, and found that it eliminated GTP. They say the findings reinforce their belief that focusing on GTP is a worthwhile pursuit that might help determine which patients will benefit most from GTP modulators in future clinical trials.

“We knew that depleting GTP might make brain cancers respond better to chemotherapy and radiation,” said Wahl. “Now, these findings show why that’s happening. When the signaling pathway is active, the cancer is resistant to radiation and chemotherapy. These findings might help us select the right patients for the next line of clinical trials.”

The study was published in the journal Cancer Discovery.

Source: Michigan Medicine – University of Michigan

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