Abstract 3101: The mutant IDH1 inhibitor prevents growth of glioblastoma with IDH1 mutation in patient-derived xenograft (PDX) model

Abstract Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are frequently observed in acute myeloid leukemia (AML), glioma, and many other cancers. While wild-type IDHs convert isocitrate to α-ketoglutarate (α-KG), mutant IDHs convert α-KG to oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of α-KG-dependent dioxygenases, such as TETs, histone demethylases, EGLNs, and other enzymes. Because the role of mutant IDH is not necessary for normal cells, inhibitors directed against mutant IDH are expected to have minimum side effects as those of anti-cancer agents. We established a mouse AML model harboring IDH mutations by co-transducing four mutant genes that frequently occur simultaneously in human AML patients. Conditional deletion of the IDH mutant blocked 2HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. These results indicate that the IDH mutations are critical for the development and maintenance of AML stem cells. Based on these findings, we developed potent and specific inhibitors of mutant IDH1 and tested their effects on the mutant IDH1-dependent AML mouse model, created by introducing four mutant genes including mutant IDH1. The 2HG level was promptly and dramatically decreased in AML cells soon after treatment with the mutant IDH1 inhibitors, and the number of leukemia cells was reduced after a 4-week treatment. To test the effect of the mutant IDH1 inhibitor on glioblastoma, we have established a patient-derived xenograft (PDX) model of glioblastoma carrying IDH1 mutation, and tested the effect of the mutant IDH1 inhibitor on this model. The inhibitor reduced 2HG levels in tumors as well as in plasma. The inhibitor prevented the growth of the tumors with IDH1 mutation. On the other hand, the inhibitor did not affect the growth of the glioblastoma with wild type IDH1. Gene expression analysis identified a set of genes, of which expressions is changed by the IDH1 inhibitor. The most strongly upregulated gene is Glial fibrillary acidic protein (GFAP), which is a differentiation marker for astrocytes. Up-regulation of GFAP is confirmed by immune-staining and quantitative RT-PCR analyses. These results suggest that IDH inhibitor induces differentiation of the glioblastoma with IDH1 mutation. We have found that the glioblastoma is transplantable in mouse brain. We are now looking at effects of the inhibitor on this model. Taken together, the results indicate that IDH1 mutant inhibitors are effective for the treatment for AML as well as glioblastoma with IDH1 mutations. Citation Format: Yukino Machida, Yoko Ogawara, Koichi Ichimura, Hironori Matsunaga, Seki Takahiko, Kazushi Araki, Issay Kitabayashi. The mutant IDH1 inhibitor prevents growth of glioblastoma with IDH1 mutation in patient-derived xenograft (PDX) model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3101.