title: Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization.
abstract: Glioblastoma (GBM) may initially respond to treatment with ionizing radiation (IR), but the prognosis remains extremely poor because the tumors invariably recur. Using animal models, we previously showed that inhibiting stromal cell-derived factor 1 signaling can prevent or delay GBM recurrence by blocking IR-induced recruitment of myeloid cells, specifically monocytes that give rise to tumor-associated macrophages. The present study was aimed at determining if inhibiting colony stimulating factor 1 (CSF-1) signaling could be used as an alternative strategy to target pro-tumorigenic myeloid cells recruited to irradiated GBM.
  
  
  
  To inhibit CSF-1 signaling in myeloid cells, we used PLX3397, a small molecule that potently inhibits the tyrosine kinase activity of the CSF-1 receptor (CSF-1R). Combined IR and PLX3397 therapy was compared with IR alone using 2 different human GBM intracranial xenograft models.
  
  
  
  GBM xenografts treated with IR upregulated CSF-1R ligand expression and increased the number of CD11b+ myeloid-derived cells in the tumors. Treatment with PLX3397 both depleted CD11b+ cells and potentiated the response of the intracranial tumors to IR. Median survival was significantly longer for mice receiving combined therapy versus IR alone. Analysis of myeloid cell differentiation markers indicated that CSF-1R inhibition prevented IR-recruited monocyte cells from differentiating into immunosuppressive, pro-angiogenic tumor-associated macrophages.
  
  
  
  CSF-1R inhibition may be a promising strategy to improve GBM response to radiotherapy.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (J.H.S., T.H., L.D., S.B.C., K.U., J.M.B.), Department of Radiation Oncology, Juntendo University School of Medicine, Tokyo, Japan (T.H.); Plexxikon Inc., Berkeley, California (B.L.W.).
authors.forename: Jason H
authors.initials: JH
authors.lastname: Stafford
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (J.H.S., T.H., L.D., S.B.C., K.U., J.M.B.), Department of Radiation Oncology, Juntendo University School of Medicine, Tokyo, Japan (T.H.); Plexxikon Inc., Berkeley, California (B.L.W.).
authors.forename: Takahisa
authors.initials: T
authors.lastname: Hirai
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (J.H.S., T.H., L.D., S.B.C., K.U., J.M.B.), Department of Radiation Oncology, Juntendo University School of Medicine, Tokyo, Japan (T.H.); Plexxikon Inc., Berkeley, California (B.L.W.).
authors.forename: Lei
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (J.H.S., T.H., L.D., S.B.C., K.U., J.M.B.), Department of Radiation Oncology, Juntendo University School of Medicine, Tokyo, Japan (T.H.); Plexxikon Inc., Berkeley, California (B.L.W.).
authors.forename: Sophia B
authors.initials: SB
authors.lastname: Chernikova
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (J.H.S., T.H., L.D., S.B.C., K.U., J.M.B.), Department of Radiation Oncology, Juntendo University School of Medicine, Tokyo, Japan (T.H.); Plexxikon Inc., Berkeley, California (B.L.W.).
authors.forename: Kimiko
authors.initials: K
authors.lastname: Urata
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (J.H.S., T.H., L.D., S.B.C., K.U., J.M.B.), Department of Radiation Oncology, Juntendo University School of Medicine, Tokyo, Japan (T.H.); Plexxikon Inc., Berkeley, California (B.L.W.).
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (J.H.S., T.H., L.D., S.B.C., K.U., J.M.B.), Department of Radiation Oncology, Juntendo University School of Medicine, Tokyo, Japan (T.H.); Plexxikon Inc., Berkeley, California (B.L.W.).
authors.forename: J Martin
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: CSF-1; angiogenesis; glioblastoma; macrophages; radiation