MODELING AND THERAPEUTIC TARGETING OF ENDOGENOUS IDH1-MUTANT GLIOMA
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Somatic mutations in Isocitrate Dehydrogenase 1 (IDH1) are frequent in low grade and progressive gliomas. IDH1 mutant tumors are phenotypically characterized by the increased production of 2-hydroxyglutarate (2-HG) from α-ketoglutarate. 2-HG is an “oncometabolite” that competitively inhibits α-KG dependent dioxygenases. The inhibition of these dioxygenases causes widespread cellular changes including abnormal hypermethylation of genomic DNA and suppression of cellular differentiation. Recent investigations of malignant gliomas have identified additional genetic and chromosomal abnormalities that cluster with IDH1 mutations into two molecularly distinct subgroups. The astrocytic subgroup is defined by frequent mutations in ATRX, TP53 and displays alternative lengthening of telomeres. The second subgroup with oligodendrocytic morphology has frequent mutations in CIC or FUBP1, and is linked to co-deletion of the 1p/19q arms. These mutations reflect the development of two distinct molecular pathways representing the majority of IDH1 mutant gliomas. Unfortunately, due to the scarcity of endogenously derived IDH1 mutant models, opportunities to evaluate therapies targeted to the mutation or its consequences have been limited. Here we report the generation of an endogenous IDH1 mutant anaplastic astrocytoma model. This novel tumor model expresses the IDH1 (R132H) mutant protein, grows rapidly in vivo, produces 2-HG, exhibits DNA hypermethylation and harbors concurrent mutations in TP53, CDKN2A and ATRX. Furthermore, this model has a similar histopathology as the original patient tumor, and exhibits an alternative lengthening of telomeres phenotype. Using this in vivo model, we have demonstrated the preclinical efficacy and mechanism of action of the FDA approved demethylating drug 5-azacytidine. Long term administration of 5-azacytidine resulted in reduction of DNA methylation of promoter loci, induction of glial differentiation, reduction of cell proliferation and a significant reduction in tumor growth. Tumors regressed by 14 weeks and subsequently showed no signs of re-growth at 7 weeks despite discontinuation of therapy. These results suggest that demethylating agents might be useful for the clinical management of patients with IDH-mutant gliomas.