title: Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma.
abstract: BACKGROUND
  Glioblastoma (GBM) is the most common and aggressive form of brain cancer. Our previous studies demonstrated that combined inhibition of HDAC and KDM1A increases apoptotic cell death in vitro. However, whether this combination also increases death of the glioma stem cell (GSC) population or has an effect in vivo is yet to be determined. Therefore, we evaluated the translational potential of combined HDAC and KDM1A inhibition on patient-derived GSCs and xenograft GBM mouse models. We also investigated the changes in transcriptional programing induced by the combination in an effort to understand the induced molecular mechanisms of GBM cell death.
  
  
  METHODS
  Patient-derived GSCs were treated with the combination of vorinostat, a pan-HDAC inhibitor, and tranylcypromine, a KDM1A inhibitor, and viability was measured. To characterize transcriptional profiles associated with cell death, we used RNA-Seq and validated gene changes by RT-qPCR and protein expression via Western blot. Apoptosis was measured using DNA fragmentation assays. Orthotopic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis and to validate gene changes in vivo.
  
  
  RESULTS
  The combination of vorinostat and tranylcypromine reduced GSC viability and displayed efficacy in the U87 xenograft model. Additionally, the combination led to changes in apoptosis-related genes, particularly TP53 and TP73 in vitro and in vivo.
  
  
  CONCLUSIONS
  These data support targeting HDACs and KDM1A in combination as a strategy for GBM and identifies TP53 and TP73 as being altered in response to treatment.
authors: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, Texas (M.M.S., B.J., J.C.); Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.V., E.R.F.); Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas (M.B., J.C.); Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas (J.Z., X.S.); Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas (B.J., F.L.); Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas (A.V., E.R.F., M.B., F.L., J.C.).
authors: Melissa M
authors: MM
authors: Singh
authors: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, Texas (M.M.S., B.J., J.C.); Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.V., E.R.F.); Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas (M.B., J.C.); Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas (J.Z., X.S.); Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas (B.J., F.L.); Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas (A.V., E.R.F., M.B., F.L., J.C.).
authors: Blake
authors: B
authors: Johnson
authors: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, Texas (M.M.S., B.J., J.C.); Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.V., E.R.F.); Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas (M.B., J.C.); Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas (J.Z., X.S.); Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas (B.J., F.L.); Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas (A.V., E.R.F., M.B., F.L., J.C.).
authors: Avinashnarayan
authors: A
authors: Venkatarayan
authors: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, Texas (M.M.S., B.J., J.C.); Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.V., E.R.F.); Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas (M.B., J.C.); Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas (J.Z., X.S.); Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas (B.J., F.L.); Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas (A.V., E.R.F., M.B., F.L., J.C.).
authors: Elsa R
authors: ER
authors: Flores
authors: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, Texas (M.M.S., B.J., J.C.); Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.V., E.R.F.); Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas (M.B., J.C.); Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas (J.Z., X.S.); Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas (B.J., F.L.); Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas (A.V., E.R.F., M.B., F.L., J.C.).
authors: Jianping
authors: J
authors: Zhang
authors: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, Texas (M.M.S., B.J., J.C.); Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.V., E.R.F.); Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas (M.B., J.C.); Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas (J.Z., X.S.); Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas (B.J., F.L.); Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas (A.V., E.R.F., M.B., F.L., J.C.).
authors: Xiaoping
authors: X
authors: Su
authors: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, Texas (M.M.S., B.J., J.C.); Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.V., E.R.F.); Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas (M.B., J.C.); Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas (J.Z., X.S.); Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas (B.J., F.L.); Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas (A.V., E.R.F., M.B., F.L., J.C.).
authors: Michelle
authors: M
authors: Barton
authors: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, Texas (M.M.S., B.J., J.C.); Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.V., E.R.F.); Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas (M.B., J.C.); Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas (J.Z., X.S.); Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas (B.J., F.L.); Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas (A.V., E.R.F., M.B., F.L., J.C.).
authors: Frederick
authors: F
authors: Lang
authors: Department of Pediatrics Research, University of Texas MD Anderson Cancer Center, Houston, Texas (M.M.S., B.J., J.C.); Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.V., E.R.F.); Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas (M.B., J.C.); Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas (J.Z., X.S.); Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas (B.J., F.L.); Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas (A.V., E.R.F., M.B., F.L., J.C.).
authors: Joya
authors: J
authors: Chandra
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation; D005260:Female; D005909:Glioblastoma / Q000473:pathology*; D059014:High-Throughput Nucleotide Sequencing; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D056466:Histone Demethylases / Q000037:antagonists & inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D059467:Transcriptome / Q000187:drug effects; D014191:Tranylcypromine / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014191:Tranylcypromine; D000077337:Vorinostat; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: HDAC inhibitors; KDM1A; LSD1; epigenetics; glioblastoma; lysine demethylases; orthotopic GBM models; tranylcypromine