title: A novel drug conjugate, NEO212, targeting proneural and mesenchymal subtypes of patient-derived glioma cancer stem cells.
abstract: Glioblastoma multiforme (GBM), a highly malignant brain tumor, accounts for half of all gliomas. Despite surgery, radiation and chemotherapy, the median survival is between 12 and 15 months. The poor prognosis is due to tumor recurrence attributed to chemoresistant glioma cancer stem cells (GSCs). Here we examined the effects of a novel compound NEO212, which is composed of two covalently conjugated anti-cancer compounds - temozolomide (TMZ) and perillyl alcohol (POH), on GSCs expressing either the proneural or mesenchymal gene signatures. These GSCs were obtained from patient-derived tumor tissue. Our findings demonstrate that NEO212 is 10 fold more cytotoxic to GSCs than TMZ (standard-of-care). Furthermore, NEO212 is effective against both proneural and clinically aggressive mesenchymal GSC subtypes. The mechanism of NEO212 mediated-cytotoxicity is through double-strand DNA breaks and apoptosis. In vivo studies show that NEO212 significantly delays tumor growth of both proneural and mesenchymal tumor stem cell populations. Patient-derived GSCs and tumors derived from these cells are highly reflective of the heterogeneity in human GBM. The efficacy of NEO212 against both GSC subtypes indicates that NEO212 has great clinical potential to effectively target GBM.
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Niyati
authors.initials: N
authors.lastname: Jhaveri
authors.affiliation: Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Agasse
authors.affiliation: University of California Riverside, USA.
authors.forename: Don
authors.initials: D
authors.lastname: Armstrong
authors.affiliation: Department of Neurosurgery, Luzhou Medical University, Sichuan, China.
authors.forename: Lilei
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Commins
authors.affiliation: Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Weijun
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Rosenstein-Sisson
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Vijaya Pooja
authors.initials: VP
authors.lastname: Vaikari
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Shayane V
authors.initials: SV
authors.lastname: Santiago
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Tiago
authors.initials: T
authors.lastname: Santos
authors.affiliation: Department of Neurosurgery, Luzhou Medical University, Sichuan, China.
authors.forename: Ligang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Axel H
authors.initials: AH
authors.lastname: Schönthal
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: tcchen@med.usc.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: hofman@usc.edu.
authors.forename: Florence M
authors.initials: FM
authors.lastname: Hofman
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053903:DNA Breaks, Double-Stranded; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000077204:Temozolomide; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; C000596794:NEO212; D003606:Dacarbazine; D000077204:Temozolomide
keywords: DNA damage; Glioblastoma; Glioma cancer stem cells; Mesenchymal; NEO212; Proneural; TMZ resistance