Drugs that target cell metabolism may lead to new treatment for childhood brain cancer

Charles Brenner, PhD

Scientists have identified a class of drugs that may have potential to treat a rare and deadly form of brain cancer that affects young children.

The research team, led by Ranjit Bindra, MD, PhD, and colleagues at the Yale Cancer Center, also included co-senior authors Charles Brenner, PhD, professor and DEO of biochemistry at the University of Iowa Carver College of Medicine, and Michael E. Berens, PhD, from the Translational Genomics Research Institute in Phoenix.

The findings, published Aug. 22 in Nature Communications, focus on Diffuse Intrinsic Pontine Glioma (DIPG), a rare, incurable cancer that affects the brainstem in children under age 10. Previous work had identified mutations in a gene called PPM1D as a cause of this cancer.

Using tumor cells and cells engineered to have PPM1D mutations, the team screened for drugs that would kill the cells. The strategy revealed an unexpected hit in the form of a drug that targets NAMPT, a protein involved in the synthesis of nicotinamide adenine dinucleotide (NAD), which is a key metabolite in cellular energy production and essential for cell function and survival.

Brenner, who developed the technology of NAD metabolomics, led the quantitative analysis of the NAD system in this genetically classified system of PPM1D mutation-positive cells. Mark Schmidt, PhD, a research associate in Brenner’s lab, was also involved in this aspect of the study.

The team discovered that the PPM1D mutations alter the cells’ epigenome in such a way that certain genes are silenced, including a gene called NAPRT, which is involved in the production of NAD.

By effectively shutting down one of the cell’s pathways for producing NAD, the PPMID mutations appears to leave the tumor cells reliant on another NAD pathway that involves the NAMPT gene. The drugs discovered in the screen targets this pathway by inhibiting NAMPT activity. 

“The study found that this type of tumor can be killed by targeting NAD production with available drugs,” Brenner says. “It’s not the first time these drugs have shown promisingly anti-cancer activity, but it is highly novel because the ‘lore’ has been that tumor cells need higher NAD. These results indicate that is not generally true. The PPM1D cells are both malignant and killable by this class of drug because they have a depressed NAD system.”

The findings suggest that other cancers that have PPM1D mutations, which include breast and gynecological cancers, may also be susceptible to this class of drug. More research is needed to determine if these drugs might benefit patients with DIPG, but as some of these types of drugs have already been tested clinically, the team is hopeful that those studies can progress.

In addition to Bindra, Brenner, and Berens, the international team included scientists from Yale University, the University of Iowa, the Translational Genomics Research Institute, the Institute of Cancer Research in London, the Institut de Recerca Sant Joan de Deu, Barcelona, Spain, and Children’s National Health System in Washington D.C.

This work was supported by funding from the National Cancer Institute, the American Cancer Society, the Yale Cancer Biology Training Program via the Yale Cancer Center and Yale School of Medicine, and philanthropic support from the Hope Through Hollis Fund in the TGen Foundation, the Whatever It Takes Foundation, the Team Cozzi Foundation and the Roy J. Carver Charitable Trust.

Date: 
Thursday, August 22, 2019