Researchers have discovered a new pathway that can attack and improve survival rate in an incurable type of brain cancer among children.
The study published in the journal 'Nature Communications,' suggested that the pathway disrupts the cellular process that contributes to Diffuse Intrinsic Pontine Gliomas (DIPG).
DIPG is a highly aggressive and inoperable type of tumour that grows in the brain stem and usually strikes children less than 10 years old. 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.
This study has discovered a vulnerability in the metabolic process for creating NAD, a metabolite that is necessary for all cell life.
"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, 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.
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.
The researchers chose to look at the tumour 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 analysed, 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, one of the study's contributing authors.
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