{"doi":"10.1016/j.tranon.2022.101368","title":"Synergistic anti-tumor efficacy of mutant isocitrate dehydrogenase 1 inhibitor SYC-435 with standard therapy in patient-derived xenograft mouse models of glioma","abstract":"Clinical outcomes in patients with WHO grade II/III astrocytoma, oligodendroglioma or secondary glioblastoma remain poor. Isocitrate dehydrogenase 1 (IDH1) is mutated in > 70% of these tumors, making it an attractive therapeutic target. To determine the efficacy of our newly developed mutant IDH1 inhibitor, SYC-435 (1-hydroxypyridin-2-one), we treated orthotopic glioma xenograft model (IC-BT142AOA) carrying R132H mutation and our newly established orthotopic patient-derived xenograft (PDX) model of recurrent anaplastic oligoastrocytoma (IC-V0914AOA) bearing R132C mutation. In addition to suppressing IDH1 mutant cell proliferation in vitro, SYC-435 (15 mg/kg, daily x 28 days) synergistically prolonged animal survival times with standard therapies (Temozolomide + fractionated radiation) mediated by reduction of H3K4/H3K9 methylation and expression of mitochondrial DNA (mtDNA)-encoded molecules. Furthermore, RNA-seq of the remnant tumors identified genes (MYO1F, CTC1 and BCL9) and pathways (base excision repair, TCA cycle II, sirtuin signaling, protein kinase A, eukaryotic initiation factor 2 and α-adrenergic signaling) as mediators of therapy resistance. Our data demonstrated the efficacy SYC-435 in targeting IDH1 mutant gliomas when combined with standard therapy and identified a novel set of genes that should be prioritized for future studies to overcome SYC-435 resistance.","journal":"Translational Oncology","year":2022,"id":245109,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":260502,"name":"Lin Qi","orcid":"0000-0003-2491-2701","position":1,"is_corresponding":false},{"id":375152,"name":"Yuchen Du","orcid":null,"position":2,"is_corresponding":false},{"id":373629,"name":"Frank Braun","orcid":"0000-0002-5514-1412","position":3,"is_corresponding":false},{"id":7836,"name":"Huiyuan Zhang","orcid":"0000-0002-1532-2462","position":4,"is_corresponding":false},{"id":258277,"name":"Lei Huang","orcid":"0000-0002-0322-6078","position":5,"is_corresponding":false},{"id":18059,"name":"Lei Guo","orcid":"0000-0002-6072-2377","position":6,"is_corresponding":false},{"id":373630,"name":"Yulun Huang","orcid":"0000-0002-5297-6967","position":7,"is_corresponding":false},{"id":373631,"name":"Wan‐Yee Teo","orcid":"0000-0002-1046-1674","position":8,"is_corresponding":false},{"id":132350,"name":"Holly B. 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