An international team of researchers led by Yale University, the University of Iowa, and the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, reports the discovery of a new pathway that may improve success against an incurable type of children’s brain cancer. The study results (“PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma”), published in Nature Communications, suggest that scientists have identified a novel way to disrupt the cellular process that contributes to Diffuse Intrinsic Pontine Gliomas (DIPG).

Brain tumour, illustration
Source: Alfred Pasieka/Science Photo LIB / Getty Images/Science Photo Library

DIPG is a highly aggressive and inoperable type of tumor that grows in the brain stem. This cancer usually strikes children less than 10 years old, and most patients do not survive more than a year after diagnosis.

Earlier studies identified a genetic mutation called PPM1D, which is critical for cell growth and cell stress response, as a contributor to DIPG. Previous efforts to directly attack the PPM1D mutation, however, proved futile in controlling DIPG.

The TGen-Yale-Iowa led team discovered a vulnerability in the metabolic process for creating nicotinamide adenine dinucleotide (NAD), a metabolite that is necessary for all cell life.

“Pediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition,” the investigators wrote.

“Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing.”

“This is really an amazing new way to attack this cancer. We found that the mutated gene PPM1D essentially sets the stage for its own demise,” said Michael Berens, PhD, a TGen deputy director, head of TGen’s DIPG research, and one of the study’s senior authors.

Researchers found that mutated PPM1D silences a gene called NAPRT, which is key to the production of the NAD metabolite. With NAPRT unavailable, the cell switches to another protein needed to create NAD called NAMPT. By using a drug that inhibits the production of NAMPT, researchers found they could essentially starve to death those cancer cells with the PPM1D mutation.

“It is such a devastating disease, and we have been so stymied in our progress for new DIPG therapies. Many drugs have been tested with no success at all. These findings now offer new hope for children with this truly terrible disease,” said another senior author Ranjit Bindra, MD, PhD, associate professor of therapeutic radiology at the Yale Cancer Center, where he treats children with DIPG.

Researchers had long thought DIPG was a childhood version of adult brain tumors, and so similar treatments for adult gliomas were tested extensively in children and failed. Scientists decided to take a different approach in the search for new drugs to treat this disease. They chose to look at the tumor in terms of its potential vulnerabilities, and thus began a year-long molecular journey to understand what role the PPM1D mutation played in altering cancer metabolism.

“When epigenetic silencing results were analyzed, we were gratified to discover that DIPG cells with the PPM1D mutation had created a vulnerability to a key enzyme for which small molecule inhibitors were already available,” said Sen Peng, PhD, a bioinformatician in TGen’s Cancer & Cell Biology Division, and one of the study’s contributing authors.

While the number of patients affected in the United States is small (about 300 annually), DIPG is recognized as a profoundly tragic illness.

“Our study’s potential translational impact should lead to clinical trials and renewed hope for these families who face such a difficult diagnosis for their child,” said Charles Brenner, PhD, chairman of biochemistry at the University of Iowa, and an expert in NAD metabolism. Brenner also was one of the study’s senior authors.

Bindra said this study suggests that other cancers with PPM1D mutations, such as breast and gynecological cancers, could be similarly targeted.

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