Abstract A144: Inhibition of 2-HG production in IDH mutant xenograft models.

Isocitrate dehydrogenase 1 and 2 (IDH1/2) oxidize isocitrateto α-ketoglutarate (α-KG), a cofactor needed for the function of over 100 enzymes1. Heterozygous mutations of IDH1/2 occur in a variety of tumor types including glioma, acute myeloid leukemia (AML), cholangiosarcoma, chondrosarcoma and melanoma2. Mutant IDH is crippled for wild-type function but gains the ability to convert α-KG to 2-hydroxyglutarate (2-HG), a believed “oncometabolite” that may alter cell biology through, in part, changes in global histone and DNA methylation 1,3,4. However, the dearth of in vivo models dependent upon mutant IDH has made understanding the biological relevance of IDH mutations and 2-HG production in cancer challenging. To better understand the role that IDH mutations play in oncogenesis, and the potential effects of inhibition of these mutations, we introduced a heterozygous point mutation of IDH1 (R132H) into the endogenous locus of the HCT116 colon carcinoma cell line. When compared with the parental IDH1 wild-type HCT116 model, HCT116 IDH1R132H/+ xenograft tumors produce significantly higher levels of 2-HG. In addition, we have identified a patient-derived melanoma model, HMEX2838, which harbors an endogenous IDH1R132C/+ mutation and expresses high levels of 2-HG. To better explore the biology of mutant IDH inhibition, we developed a mutant-selective IDH inhibitor with favorable in vivo properties. Using this compound we demonstrate that 2-HG production is strongly inhibited in both the engineered HCT116 IDH1R132H/+ xenograft model and the endogenously mutant HMEX2838 patient-derived xenograft model. The data we have generated suggests that this inhibition of 2-HG directly correlates with the area under the curve (AUC) of free-drug above the HCT116 IDH1R132H/+ cellular IC50, as determined in vitro. Using these models and our IDH inhibitors we hope to gain a better understanding of how IDH mutations contribute to cancer and how inhibition of the mutant enzyme could benefit patients. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A144. Citation Format: Kelly L. Slocum, Julia Downall, Ty Gould, Mohammad Zafari, Stephanie Dodd, Brant Firestone, Ray Pagliarini, Julian Levell. Inhibition of 2-HG production in IDH mutant xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A144.