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Developmental Biology - Glioma
Unique Treatment For DPIG Glioma
Genomic bait and switch starves mutation that contributes to Diffuse Intrinsic Pontine Gliomas (DIPG)...
An international team of researchers led by Yale University, University of Iowa, and the Translational Genomics Research Institute (TGen) - an affiliate of the City of Hope - has discovered a new pathway that may improve success against an incurable type of children's brain cancer.
The study results, published in Nature Communications, suggest researchers have identified a unique way to disrupt the cellular process that contributes to Diffuse Intrinsic Pontine Gliomas (DIPG).
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 - critical for cell growth and cell stress response - as contributing to DIPG. Previous efforts to directly attack the PPM1D mutation, however, proved futile for controlling DIPG.
Then the TGen-Yale-Iowa led team discovered a vulnerability in the metabolic process. NAD is a metabolite needed for all cell life. Researchers found that mutated PPM1D silences a gene called NAPRT — key to production of the NAD metabolite. With NAPRT unavailable, the cell switches to another protein needed to create NAD called NAMPT. Using a drug to inhibit production of NAMPT, researchers essentially starved cancer cells with the PPM1D mutation.
"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."
Michael Berens PhD, a TGen Deputy Director, Head, TGen's DIPG Research, and one of the study's senior authors.
"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," adds senior author Ranjit Bindra MD PhD, and 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.
Frustration over the lack of an effective therapy led researchers to take a different approach. They chose to look at the tumor in terms of its potential vulnerabilities, and began a year-long molecular journey to understand what role the PPM1D mutation plays in altering cancer metabolism.
"When epigenetic silencing results were analyzed, we were gratified to discover that DIPG cells with the PPM1D mutation had a vulnerability to a key enzyme — for which small molecule inhibitors were already available," explains Sen Peng PhD, and bioinformatician with TGen Cancer & Cell Biology Division, also a contributing author.
Today, Dr. Bindra feels the study suggests other cancers with PPM1D mutations — such as breast and gynecological cancers — could be similarly targeted.
"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, an expert in nicotinamide adenine dinucleotide (NAD) metabolism and one of the study's senior authors.
While the number of patients affected in the U.S. is small - about 300 annually - DIPG is recognized as a profoundly tragic illness.
Abstract
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. 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.
Authors
Nathan R. Fons, Ranjini K. Sundaram, Gregory A. Breuer, Sen Peng, Ryan L. McLean, Aravind N. Kalathil, Mark S. Schmidt, Diana M. Carvalho, Alan Mackay, Chris Jones, Ángel M. Carcaboso, Javad Nazarian, Michael E. Berens, Charles Brenner & Ranjit S. Bindra.
Acknowledgements
The authors would like to thank Drs. Timothy Chan, Ryan Jensen, Peter Glazer, and Michelle Monje for cell lines and reagents. This work was supported by funding from the NIH (5RO1CA215453-02 to R.S.B.), the American Cancer Society (128352-RSG-15-197-01 to R.S.B.), the Yale Cancer Biology Training Program via the Yale Cancer Center and Yale School of Medicine (N.R.F.), and philanthropic support from the Hope Through Hollis Fund in the TGen Foundation, the Whatever It Takes Foundation, the Team Cozzi Foundation (S.P. and M.E.B.), and the Roy J. Carver Trust (CB).
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Aug 26 2019 Fetal Timeline Maternal Timeline News
 Diffuse Intrinsic Pontine Glioma, or DIPG, is an extremely rare pediatric brain tumor that typically strikes between the ages of 5 and 10, infiltrating the brain stem, with a 0% survival rate. McKenna was 7 when diagnosed in 2011, and died two weeks shy of her eighth birthday and exactly six months from her diagnosis. CREDIT Kristine Wetzel, St. Baldrick's Foundation.
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