Translational Oncology (Apr 2022)
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
Affiliations
- Mari Kogiso
- 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
- Lin Qi
- 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
- Yuchen Du
- 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
- Frank K. Braun
- 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
- Huiyuan Zhang
- 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
- L. Frank Huang
- 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
- Lei Guo
- Texas A&M Health Science Center, Institute of Biosciences and Technology, Houston, TX 77030, USA
- Yulun Huang
- 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
- Wan-Yee Teo
- 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
- Holly Lindsay
- 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
- Sibo Zhao
- 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
- Sarah G. Injac
- 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
- Zhen Liu
- Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA
- Vidya Mehta
- Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
- Diep Tran
- Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
- Feng Li
- Department of Pathology, Alkek Center for Drug Discovery, Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA
- Patricia A. Baxter
- Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA
- Jack M. Su
- Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA
- Laszlo Perlaky
- Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA
- D. Williams Parsons
- Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA
- Murali Chintagumpala
- Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA
- Adekunle Adesina
- Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
- Yongcheng Song
- Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA
- Xiao-Nan Li
- 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; Corresponding author: Xiao-Nan Li, M.D., Ph.D., Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Ann & Robert H. Lurie Children's Hospital of Chicago; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Simpson Querrey Biomedical Research Center, 4th floor, Room 4-522, 303 E. Superior St, Chicago, IL 60611; Phone: 312-503-6396.
- Journal volume & issue
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Vol. 18
p. 101368
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.
