title: Evidence for new targets and synergistic effect of metronomic celecoxib/fluvastatin combination in pilocytic astrocytoma.
abstract: BACKGROUND
  Pilocytic astrocytomas occur predominantly in childhood. In contrast to the posterior fossa location, hypothalamo-chiasmatic pilocytic astrocytomas display a worse prognosis often leading to multiple surgical procedures and/or several lines of chemotherapy and radiotherapy to achieve long-term control. Hypothalamo-chiasmatic pilocytic astrocytomas and cerebellar pilocytic astrocytomas have a distinctive gene signature and several differential expressed genes (ICAM1, CRK, CD36, and IQGAP1) are targets for available drugs: fluvastatin and/or celecoxib.
  
  
  RESULTS
  Quantification by RT-Q-PCR of the expression of these genes was performed in a series of 51 pilocytic astrocytomas and 10 glioblastomas: they were all significantly overexpressed in hypothalamo-chiasmatic pilocytic astrocytomas relative to cerebellar pilocytic astrocytomas, and CRK and ICAM1 were significantly overexpressed in pilocytic astrocytomas versus glioblastomas.We used two commercially available glioblastoma cell lines and three pilocytic astrocytoma explant cultures to investigate the effect of celecoxib/fluvastatin alone or in combination. Glioblastoma cell lines were sensitive to both drugs and a combination of 100 μM celecoxib and 240 μM fluvastatin was the most synergistic. This synergistic combination was used on the explant cultures and led to massive cell death of pilocytic astrocytoma cells.As a proof of concept, a patient with a refractory multifocal pilocytic astrocytoma was successfully treated with the fluvastatin/celecoxib combination used for 18 months. It was well tolerated and led to a partial tumor response.
  
  
  CONCLUSIONS
  This study reports evidence for new targets and synergistic effect of celecoxib/fluvastatin combination in pilocytic astrocytoma. Because it is non-toxic, this new strategy offers hope for the treatment of patients with refractory pilocytic astrocytoma.
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR_S 911, 27 bd Jean Moulin, 13385, Marseille, cedex 05, France. dominique.figarella-branger@univ-amu.fr.
authors.forename: Sandy
authors.initials: S
authors.lastname: Mercurio
authors.forename: Laetitia
authors.initials: L
authors.lastname: Padovani
authors.forename: Carole
authors.initials: C
authors.lastname: Colin
authors.forename: Manon
authors.initials: M
authors.lastname: Carré
authors.forename: Aurélie
authors.initials: A
authors.lastname: Tchoghandjian
authors.forename: Didier
authors.initials: D
authors.lastname: Scavarda
authors.forename: Sally
authors.initials: S
authors.lastname: Lambert
authors.forename: Nathalie
authors.initials: N
authors.lastname: Baeza-Kallee
authors.forename: Carla
authors.initials: C
authors.lastname: Fernandez
authors.forename: Céline
authors.initials: C
authors.lastname: Chappé
authors.forename: Nicolas
authors.initials: N
authors.lastname: André
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D001254:Astrocytoma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018955:CD36 Antigens / Q000378:metabolism; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002675:Child, Preschool; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004357:Drug Synergism; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D000077340:Fluvastatin; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D046509:Tissue Culture Techniques; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; C485285:CRK protein, human; D052246:Cyclooxygenase 2 Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C573420:ICAM1 protein, human; C101203:IQ motif containing GTPase activating protein 1; D007211:Indoles; D050737:Proto-Oncogene Proteins c-crk; D011720:Pyrazoles; D013449:Sulfonamides; D020703:ras GTPase-Activating Proteins; D018799:Intercellular Adhesion Molecule-1; D000077340:Fluvastatin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib