title: Response of primary glioblastoma cells to therapy is patient specific and independent of cancer stem cell phenotype.
abstract: BACKGROUND
  Glioblastoma multiforme (GBM) contains a population of cells that exhibit stem cell phenotypes. These cancer stem cells (CSCs) may be a source of therapeutic resistance, although support for this important concept is limited.
  
  
  METHODS
  We determined whether early-passage GBM CSCs respond differently than patient-matched, genotypically similar non-CSCs to clinically relevant single or serial doses of temozolomide (TMZ), radiation therapy (XRT), or alternating TMZ treatment and XRT, which is the standard of care for GBM patients.
  
  
  RESULTS
  Despite the phenotypic differences, including the presence of stem cell markers and formation of intracranial tumors, the CSCs and matched non-CSCs were equally resistant to TMZ in a majority of patients, using 2 independent assays. TMZ response was consistent with methylated O(6)-DNA methylguanine-methyltransferase (MGMT) and MGMT protein levels in both culture types. In contrast, CSCs were unexpectedly more responsive to XRT compared with matched non-CSCs from 2 patients despite having relatively equal resistance to TMZ. However, for the majority of culture pairs from individual patients, responses in CSCs were indistinguishable from non-CSC cultures.
  
  
  CONCLUSIONS
  In our patient-matched primary cultures, response to TMZ was tightly linked to the individual tumor's MGMT status and independent of their phenotypic differences. TMZ and XRT together revealed no additive benefit compared with monotherapy for either culture type, in contrast to the notion that the CSC population is more resistant to XRT. If the tumor cell response in vitro mirrors therapeutic response in larger patient cohorts, these rapid assays in primary cultures could allow -empirical selection of efficacious therapeutic agents on a patient-specific basis.
authors: Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, San Francisco, California (S.D.F., C.D.J., S.C., J.F.C); Department of Radiation Oncology, University of California, San Francisco, California (J.L.N.).
authors: Shaun D
authors: SD
authors: Fouse
authors: Jean L
authors: JL
authors: Nakamura
authors: C David
authors: CD
authors: James
authors: Susan
authors: S
authors: Chang
authors: Joseph F
authors: JF
authors: Costello
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000628:therapy*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005909:Glioblastoma / Q000628:therapy*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000528:radiation effects*; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018906:Antineoplastic Agents, Alkylating; D006023:Glycoproteins; D010455:Peptides; D003606:Dacarbazine; D000077204:Temozolomide
keywords: cancer stem cell; glioblastoma multiforme; radiation response