Abstract 3870: The addition of CB-839 to temozolomide significantly reduces glioma aspartate and glutamate in an IDH mutated patient derived glioma xenograft model

Abstract

Background: IDH mutated gliomas are critically dependent on glutaminase for glutamate biosynthesis. CB-839 is a novel glutaminase-1 inhibitor which has demonstrated efficacy in both genetically engineered and patient derived IDH mutated glioma cells, especially in combination with radiation. These preclinical studies evaluate the pharmacodynamic and pharmacokinetic impact of combining CB-839 with TMZ in patient derived xenograft (PDX) glioma models. Methods: GBM164 is a PDX model derived from an IDH1 mutant, 1p/19q non-codeleted glioma. D- and L-2HG levels in untreated GBM164 tumors were compared to GBM6 tumors (IDH wildtype glioma PDX) by GC/MS. Athymic nude mice bearing GBM164 flank tumors were treated with CB-839 (200 mg/kg PO BID x 9 doses) and/or temozolomide (50 mg/kg PO daily x 5 doses) and sacrificed four hours after the last dose to harvest plasma, normal brain and flank tumor. Tumor metabolomics were assessed by GC/MS. DNA damage signaling in tumors was assessed by Western blotting for KAP1 / Chk1 / Chk2 phosphorylation and H2AX / Rad51. Tumor, plasma and brain pharmacokinetics were assessed by LC/MS/MS. Results: Total 2HG levels in GBM164 were 18-fold higher than GBM6. CB-839 monotherapy reduced tumor glutamate (18% reduction, p = 0.15) and aspartate (30% reduction, p = 0.06) when compared to vehicle, however these changes did not reach statistical significance. The combination of CB-839 and TMZ more significantly reduced both tumor glutamate (30% reduction, p = 0.03) and aspartate (34% reduction, p < 0.001) when compared to TMZ monotherapy. CB-839 did not significantly increase DNA damage compared to vehicle, and the combination of CB-839 and TMZ did not significantly increase DNA damage compared to TMZ monotherapy. The mean tumor: plasma ratios of CB-839 concentrations were 0.68 and 0.58 in mice treated with CB-839 monotherapy and CB-839/TMZ, respectively. The mean brain: plasma ratios of CB-839 concentrations were 0.07 and 0.12 in mice treated with CB-839 monotherapy and CB-839/TMZ, respectively. Conclusion: The addition of CB-839 to TMZ significantly reduces glioma aspartate and glutamate in an IDH1 mutant PDX glioma model, without any impact on DNA damage. Survival studies are in progress to assess the efficacy of CB-839 when used in combination with RT and/or TMZ. Citation Format: Sani Haider Kizilbash, Danielle M. Burgenske, Samuel McBrayer, Sandhya Devarajan, Shiv K. Gupta, Taro Hitosugi, Lihong He, Mark A. Schroeder, Brett L. Carlson, Marina Gelman, Charles A. Kunos, Joel M. Reid, Alex A. Adjei, Jann N. Sarkaria. The addition of CB-839 to temozolomide significantly reduces glioma aspartate and glutamate in an IDH mutated patient derived glioma xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3870.