title: Farnesyl transferase expression determines clinical response to the docetaxel-lonafarnib combination in patients with advanced malignancies.
abstract: BACKGROUND
  Lonafarnib (LNF) is a protein farnesyl transferase (FTase) inhibitor that has shown synergistic activity with taxanes in preclinical models and early stage clinical trials. Preclinical findings suggested tubulin acetylation and FTase expression levels may be important determinants of drug sensitivity that would help identify patient populations more likely to benefit from this regimen. This pilot study evaluated the biological effects of LNF and docetaxel (DTX) combination therapy in refractory solid tumors by comparing pretreatment and post-treatment tumor biopsies.
  
  
  METHODS
  Patients with histologically confirmed locally advanced or metastatic solid malignancies refractory to standard therapies or with no effective therapies available were eligible. Patients were randomized to 1 of 4 dosing cohorts: 1) 30 mg/m², 100 mg; 2) 36 mg/m², 100 mg; 3) 30 mg/m², 150 mg; or 4) 36 mg/m², 150 mg of DTX intravenously weekly, LNF orally twice daily, respectively.
  
  
  RESULTS
  Of the 38 patients enrolled, 36 were treated, and 29 were evaluable for toxicity and response assessment. The combination of LNF and DTX was tolerated in all cohorts with the exception of a 28% incidence of grade 3/4 diarrhea, which was manageable with aggressive antidiarrheal regimens. Seven patients derived clinically meaningful benefit from this combination treatment; these patients had significantly lower basal FTase-beta mRNA expression levels than the mean study population level (P < .05). Correlation of clinical benefit with tubulin acetylation content as well as basal acetyl-tubulin content were evaluated. However, no significant correlation was found.
  
  
  CONCLUSIONS
  Despite the small number of patients, these findings support our preclinical mechanistic studies and warrant further clinical investigations using FTase-beta mRNA expression as a potential predictive biomarker to select for an enriched patient population to study the effects of taxane and FTase inhibitor combination therapies.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kauh
authors.forename: Chantal
authors.initials: C
authors.lastname: Chanel-Vos
authors.forename: Daniel
authors.initials: D
authors.lastname: Escuin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fanucchi
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
authors.forename: Nabil
authors.initials: N
authors.lastname: Saba
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Anthony
authors.initials: A
authors.lastname: Gal
authors.forename: Lin
authors.initials: L
authors.lastname: Pan
authors.forename: Michael
authors.initials: M
authors.lastname: Kutner
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: Laura
authors.initials: L
authors.lastname: Bender
authors.forename: Adam
authors.initials: A
authors.lastname: Marcus
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Giannakakou
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077143:Docetaxel; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010865:Pilot Projects; D010880:Piperidines / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*; D003986:Dibenzocycloheptenes
chemical_list: D000077143:Docetaxel; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D010880:Piperidines; D011725:Pyridines; D043823:Taxoids; C115354:lonafarnib; D003986:Dibenzocycloheptenes