title: Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-β Small Molecule Inhibitor.
abstract: High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-β (TGF-β) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-β signaling, indicated variable levels of TGF-β pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-β during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-β type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of γ-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-β signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients.
authors.affiliation: Department of Neurosurgery, NYU School of Medicine; Kimmel Center for Stem Cell Biology, NYU School of Medicine.
authors.forename: N Sumru
authors.initials: NS
authors.lastname: Bayin
authors.affiliation: Department of Radiation Oncology, University of California, San Francisco.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Pathology, NYU School of Medicine.
authors.forename: Cheddhi
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Department of Pathology, NYU School of Medicine.
authors.forename: Rabaa
authors.initials: R
authors.lastname: Baitalmal
authors.affiliation: Department of Neurosurgery, NYU School of Medicine.
authors.forename: Akhila
authors.initials: A
authors.lastname: Sure
authors.affiliation: Department of Neurosurgery, NYU School of Medicine.
authors.forename: Kush
authors.initials: K
authors.lastname: Fansiwala
authors.affiliation: Department of Neurosurgery, NYU School of Medicine.
authors.forename: Mark
authors.initials: M
authors.lastname: Bustoros
authors.affiliation: Department of Neurosurgery, NYU School of Medicine; Perlmutter Cancer Center, NYU School of Medicine; Brain Tumor Center, NYU School of Medicine.
authors.forename: John G
authors.initials: JG
authors.lastname: Golfinos
authors.affiliation: Department of Neurosurgery, NYU School of Medicine.
authors.forename: Donato
authors.initials: D
authors.lastname: Pacione
authors.affiliation: Department of Pathology, NYU School of Medicine; Perlmutter Cancer Center, NYU School of Medicine; Brain Tumor Center, NYU School of Medicine.
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.affiliation: Department of Pathology, NYU School of Medicine; Perlmutter Cancer Center, NYU School of Medicine; Brain Tumor Center, NYU School of Medicine.
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
authors.affiliation: Department of Radiation Oncology, University of California, San Francisco. Electronic address: mary.barcellos-hoff@ucsf.edu.
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
authors.affiliation: Department of Neurosurgery, NYU School of Medicine; Kimmel Center for Stem Cell Biology, NYU School of Medicine; Perlmutter Cancer Center, NYU School of Medicine; Brain Tumor Center, NYU School of Medicine. Electronic address: Dimitris.Placantonakis@nyumc.org.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Placantonakis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D060787:Neoplasm Grading; D057285:Precision Medicine; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014965:X-Rays
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D055748:SOXB1 Transcription Factors; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta