title: αvβ3 Integrin and Fibroblast growth factor receptor 1 (FGFR1): Prognostic factors in a phase I-II clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma.
abstract: BACKGROUND
  Based on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway.
  
  
  METHODS
  Patients were treated with 200mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvβ3, αvβ5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome.
  
  
  RESULTS
  For the phase II patients median TTP was 23.1 weeks (95%CI = [15.4; 28.2]) while the median OS was 80.3 weeks (95%CI = [57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4 w (95%CI = [47.3; 97.6]) while median TTP was 18.1 w (95%CI = [16.9; 25.6]). FGFR1 over-expression (HR = 4.65; 95%CI = [1.02; 21.21], p = 0.047) was correlated with shorter TTP while FGFR1 (HR = 4.1 (95% CI = [1.09-15.4]; p = 0.036)) and αvβ3 (HR = 10.38 (95%CI = [2.70; 39.87], p = 0.001)) over-expressions were associated with reduced OS.
  
  
  CONCLUSIONS
  Association of 200mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvβ3 integrin are independent bad prognostic factors of OS and TTP.
authors.affiliation: Institut Claudius Regaud, Département de Radiothérapie, Toulouse F-31000, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Ducassou
authors.affiliation: CHU de Toulouse, Service d'Anatomie Pathologique, Hôpital de Rangueil, Toulouse F-31000, France; Université Paul Sabatier, Toulouse F-31000, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Uro-Coste
authors.affiliation: Centre Jean Perrin, Département de Radiothérapie, Clermont-Ferrand 63000, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Verrelle
authors.affiliation: Institut Claudius Regaud, Bureau des Etudes Cliniques, Toulouse F-31000, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.affiliation: Institut Claudius Regaud, Département d'Oncologie Médicale, Toulouse F-31000, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Benouaich-Amiel
authors.affiliation: CHU de Toulouse, Service de Neurochirurgie, Hôpital de Rangueil, Toulouse F-31000, France; Université Paul Sabatier, Toulouse F-31000, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lubrano
authors.affiliation: CHU de Toulouse, Service de Neurochirurgie, Hôpital de Rangueil, Toulouse F-31000, France; Université Paul Sabatier, Toulouse F-31000, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sol
authors.affiliation: CHU de Toulouse, Service d'Anatomie Pathologique, Hôpital de Rangueil, Toulouse F-31000, France; Université Paul Sabatier, Toulouse F-31000, France.
authors.forename: Marie-Bernadette
authors.initials: MB
authors.lastname: Delisle
authors.affiliation: INSERM, Unité 1037, CRCT, Toulouse F-31000, France; Université Paul Sabatier, Toulouse F-31000, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Favre
authors.affiliation: Institut Claudius Regaud, Département de Radiothérapie, Toulouse F-31000, France.
authors.forename: Solea
authors.initials: S
authors.lastname: Ken
authors.affiliation: Institut Claudius Regaud, Département de Radiothérapie, Toulouse F-31000, France; Université Paul Sabatier, Toulouse F-31000, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Laprie
authors.affiliation: Janssen Research & Development, Turnhoutseweg 23, Beerse B-2340, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Porre
authors.affiliation: INSERM, Unité 1037, CRCT, Toulouse F-31000, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Toulas
authors.affiliation: Institut Claudius Regaud, Bureau des Etudes Cliniques, Toulouse F-31000, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Poublanc
authors.affiliation: Institut Claudius Regaud, Département de Radiothérapie, Toulouse F-31000, France; Université Paul Sabatier, Toulouse F-31000, France; INSERM, Unité 1037, CRCT, Toulouse F-31000, France. Electronic address: moyal.elizabeth@claudiusregaud.fr.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cohen-Jonathan Moyal
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism; D016896:Treatment Outcome; D000099200:Scaffold Protein ILK
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D016222:Fibroblast Growth Factor 2; D051417:Focal Adhesion Kinase 1; D039302:Integrin alphaVbeta3; D017346:Protein Serine-Threonine Kinases; D015363:Quinolones; D011838:Radiation-Sensitizing Agents; D051496:Receptor, Fibroblast Growth Factor, Type 1; D019030:Receptors, Vitronectin; D000099200:Scaffold Protein ILK; C064660:integrin alphaVbeta5; C496050:PTK2 protein, human; C402769:tipifarnib