title: Pharmacological Targeting of the Histone Chaperone Complex FACT Preferentially Eliminates Glioblastoma Stem Cells and Prolongs Survival in Preclinical Models.
abstract: The nearly universal recurrence of glioblastoma (GBM) is driven in part by a treatment-resistant subpopulation of GBM stem cells (GSC). To identify improved therapeutic possibilities, we combined the EGFR/HER2 inhibitor lapatinib with a novel small molecule, CBL0137, which inhibits FACT (facilitates chromatin transcription), a histone chaperone complex predominantly expressed in undifferentiated cells. Lapatinib and CBL0137 synergistically inhibited the proliferation of patient-derived GBM cells. Compared with non-stem tumor cells (NSTC) enriched from the same specimens, the GSCs were extremely sensitive to CBL0137 monotherapy or FACT knockdown. FACT expression was elevated in GSCs compared with matched NSTCs and decreased in GSCs upon differentiation. Acute exposure of GSCs to CBL0137 increased asymmetric cell division, decreased GSC marker expression, and decreased the capacity of GSCs to form tumor spheres in vitro and to initiate tumors in vivo Oral administration of CBL0137 to mice bearing orthotopic GBM prolonged their survival. Knockdown of FACT reduced the expression of genes encoding several core stem cell transcription factors (SOX2, OCT4, NANOG, and OLIG2), and FACT occupied the promoters of these genes. FACT expression was elevated in GBM tumors compared with non-neoplastic brain tissues, portended a worse prognosis, and positively correlated with GSC markers and stem cell gene expression signatures. Preferential targeting of GSCs by CBL0137 and synergy with EGFR inhibitors support the development of clinical trials combining these two agents in GBM. Cancer Res; 76(8); 2432-42. ©2016 AACR.
authors.affiliation: Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio. Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Josephine Kam Tai
authors.initials: JK
authors.lastname: Dermawan
authors.affiliation: Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hitomi
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Silver
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Poorva
authors.initials: P
authors.lastname: Sandlesh
authors.affiliation: Brain Tumor and Neuro-Oncology Center and Department of Neurological Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Sloan
authors.affiliation: Cleveland BioLabs Inc., Buffalo, New York.
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Purmal
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Katerina V
authors.initials: KV
authors.lastname: Gurova
authors.affiliation: Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio. Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. starkg@ccf.org monica.venere@osumc.edu.
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
authors.affiliation: Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio. Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University Wexner School of Medicine, Columbus, Ohio. starkg@ccf.org monica.venere@osumc.edu.
authors.forename: Monica
authors.initials: M
authors.lastname: Venere
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002227:Carbazoles / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006609:High Mobility Group Proteins / Q000187:drug effects*; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D011799:Quinazolines / Q000494:pharmacology; D035602:Transcriptional Elongation Factors / Q000187:drug effects*
chemical_list: C000600493:CBLC137; D002227:Carbazoles; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D011799:Quinazolines; C073537:SSRP1 protein, human; D035602:Transcriptional Elongation Factors; D000077341:Lapatinib