Jacob Paris

Introduction: Pediatric high-grade gliomas (pHGG) are the most common central nervous system tumors diagnosed in children and have a very poor prognosis. This diagnosis has a typical post-diagnosis survival of 5.6 months after intervention^1-3. New research has shown that the classification of these tumors by gene mutations shows specific markers that significantly differ from their adult counterparts⁴. These mutations could be the reason for the poor efficacy of the current standard of care, including radiation, surgical removal, and chemotherapy, which is effective in the adult disease. One of the most well-studied mutations in the pediatric population is the isocitrate dehydrogenase – 1(IDH-1) mutant disease state, which produces the oncometabolite 2-hydroxyglutarate (2-HG). 2-HG has major effects on the cellular metabolism within the tumor, as it readily affects the fate of alpha-ketoglutarate () and lowers each of its potential end products. 2-HG is a structural analog of  and thus alters the activity of enzymes involved in its metabolism via competitive inhibition⁵. Methods: Studies of other tumors focused on this mutant type have identified epigenetic alterations that function through the hydroxymethylation which silences IDH and TET (translocation dioxygenase ten-eleven) genes, exhibiting that the landscape of IDH activity is greatly impacted by the tumor’s genetic code itself ^6-11. Research has shown that this genetic silencing can be slowed by IDH-1 mutant inhibitors in in-vivo animal studies and in-vitro studies of known chondrosarcoma cell lines. Results: The novel drug DS-1001b used in this study effectively inhibited cell division by causing arrest in the G1-S phase of the cell cycle. This proved to significantly limit the growth of the chondrosarcomas after 9 weeks of treatment and appreciably lower the levels of 2-HG in less than 4 weeks of use¹². However, this treatment mechanism was not effective in reducing tumor burden in cells without the IDH-1 mutant genotype. Conclusion: pHGG could see similar effects as mutant IDH chondrosarcomas due to the synthesis of the same oncometabolite 2-HG. Additionally, pHGG genotypes have been well characterized and can be screened for the proper IDH mutant genotype prior to treatment, thereby avoiding ineffective use on wild-type tumors¹³. For these reasons, the treatment mechanism of oncometabolite targeted therapy may help improve upon the dismal patient survival associated with pHGG and its current therapeutic techniques.

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