Synergistic anti-tumor efficacy of mutant isocitrate dehydrogenase 1 inhibitor SYC-435 with standard therapy in patient-derived xenograft mouse models of glioma

Mari Kogiso; Lin Qi; Yuchen Du; Frank K Braun; Huiyuan Zhang; L Frank Huang; Lei Guo; Yulun Huang; Wan-Yee Teo; Holly Lindsay; Sibo Zhao; Sarah G Injac; Zhen Liu; Vidya Mehta; Diep Tran; Feng Li; Patricia A Baxter; Jack M Su; Laszlo Perlaky; D Williams Parsons; Murali Chintagumpala; Adekunle Adesina; Yongcheng Song; Xiao-Nan Li

doi:10.1016/j.tranon.2022.101368

Synergistic anti-tumor efficacy of mutant isocitrate dehydrogenase 1 inhibitor SYC-435 with standard therapy in patient-derived xenograft mouse models of glioma

Transl Oncol. 2022 Apr:18:101368. doi: 10.1016/j.tranon.2022.101368. Epub 2022 Feb 16.

Authors

Mari Kogiso¹, Lin Qi², Yuchen Du², Frank K Braun¹, Huiyuan Zhang¹, L Frank Huang³, Lei Guo⁴, Yulun Huang⁵, Wan-Yee Teo⁶, Holly Lindsay¹, Sibo Zhao¹, Sarah G Injac¹, Zhen Liu⁷, Vidya Mehta⁸, Diep Tran⁸, Feng Li⁹, Patricia A Baxter¹⁰, Jack M Su¹⁰, Laszlo Perlaky¹⁰, D Williams Parsons¹⁰, Murali Chintagumpala¹⁰, Adekunle Adesina⁸, Yongcheng Song⁷, Xiao-Nan Li¹¹

Affiliations

¹ Laboratory of Molecular Neuro-Oncology, Department of Pediatrics, Preclinical Neuro-Oncology Research Program, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA.
² Laboratory of Molecular Neuro-Oncology, Department of Pediatrics, Preclinical Neuro-Oncology Research Program, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Simpson Querrey Biomedical Research Center, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
³ Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
⁴ Texas A&M Health Science Center, Institute of Biosciences and Technology, Houston, TX 77030, USA.
⁵ Laboratory of Molecular Neuro-Oncology, Department of Pediatrics, Preclinical Neuro-Oncology Research Program, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neurosurgery, Brain and Nerve Research Laboratory, the First Affiliated Hospital, Soochow University Medical School, Suzhou, Jiangsu 215007, China.
⁶ Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, National Cancer Center, KK Women's and Children's Hospital, Humphrey Oei Institute of Cancer Research, Institute of Molecular and Cell Biology, A*STAR, 169610, Singapore.
⁷ Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
⁸ Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
⁹ Department of Pathology, Alkek Center for Drug Discovery, Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁰ Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA.
¹¹ Laboratory of Molecular Neuro-Oncology, Department of Pediatrics, Preclinical Neuro-Oncology Research Program, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Simpson Querrey Biomedical Research Center, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: XLi@luriechildrens.org.

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.

Keywords: Glioma; IDH1; Orthotopic PDX; SYC-435; Standard therapy.

Abstract

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