title: Prolonged inhibition of glioblastoma xenograft initiation and clonogenic growth following in vivo Notch blockade.
abstract: OBJECTIVE
  To examine the effects of clinically relevant pharmacologic Notch inhibition on glioblastoma xenografts.
  
  
  METHODS
  Murine orthotopic xenografts generated from temozolomide-sensitive and -resistant glioblastoma neurosphere lines were treated with the γ-secretase inhibitor MRK003. Tumor growth was tracked by weekly imaging, and the effects on animal survival and tumor proliferation were assessed, along with the expression of Notch targets, stem cell, and differentiation markers, and the biology of neurospheres isolated from previously treated xenografts and controls.
  
  
  RESULTS
  Weekly MRK003 therapy resulted in significant reductions in growth as measured by imaging, as well as prolongation of survival. Microscopic examination confirmed a statistically significant reduction in cross-sectional tumor area and mitotic index in a MRK003-treated cohort as compared with controls. Expression of multiple Notch targets was reduced in the xenografts, along with neural stem/progenitor cell markers, whereas glial differentiation was induced. Neurospheres derived from MRK003-treated xenografts exhibited reduced clonogenicity and formed less aggressive secondary xenografts. Neurospheres isolated from treated xenografts remained sensitive to MRK003, suggesting that therapeutic resistance does not rapidly arise during in vivo Notch blockade.
  
  
  CONCLUSIONS
  Weekly oral delivery of MRK003 results in significant in vivo inhibition of Notch pathway activity, tumor growth, stem cell marker expression, and clonogenicity, providing preclinical support for the use of such compounds in patients with malignant brain tumors. Some of these effects can persist for some time after in vivo therapy is complete.
authors: Department of Oncology, Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, China.
authors: Qian
authors: Q
authors: Chu
authors: Brent A
authors: BA
authors: Orr
authors: Samantha
authors: S
authors: Semenkow
authors: Eli E
authors: EE
authors: Bar
authors: Charles G
authors: CG
authors: Eberhart
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077204:Temozolomide; D013830:Thiadiazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D003499:Cyclic S-Oxides; C523799:MRK 003; D051880:Receptors, Notch; D013830:Thiadiazoles; D003606:Dacarbazine; D053829:Amyloid Precursor Protein Secretases; D000077204:Temozolomide
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