title: Response of the insulin-like growth factor (IGF) system to IGF-IR inhibition and androgen deprivation in a neoadjuvant prostate cancer trial: effects of obesity and androgen deprivation.
abstract: BACKGROUND
  Prostate cancer patients at increased risk for relapse after prostatectomy were treated in a neoadjuvant study with androgen deprivation therapy (ADT) in combination with cixutumumab, an inhibitory fully human monoclonal antibody against IGF receptor 1 (IGF-IR).
  
  
  OBJECTIVE
  A clinical trial with prospective collection of serum and tissue was designed to test the potential clinical efficacy of neoadjuvant IGF-IR blockade combined with ADT in these patients. The effect of body mass index (BMI) on response of IGF-IR/insulin components to IGF-IR blockade was also examined.
  
  
  METHODS
  Eligibility for the trial required the presence of high-risk prostate adenocarcinoma. Treatment consisted of bicalutamide, goserelin, and cixutumumab for 13 weeks before prostatectomy. Here we report on an analysis of serum samples from 29 enrolled patients. Changes in IGF and glucose homeostasis pathways were compared to control samples from patients in a concurrent clinical trial of neoadjuvant ADT alone.
  
  
  RESULTS
  Significant increases were seen in GH (P = .001), IGF-I (P < .0001), IGF-II (P = .003), IGF binding protein (IGFBP)-3 (P < .0001), C-peptide (P = .0038), and insulin (P = .05) compared to patients treated with ADT alone. IGFBP-1 levels were significantly lower in the cixutumumab plus ADT cohort (P = .001). No significant changes in blood glucose were evident. Patients with BMIs in the normal range had significantly higher GH (P < .05) and IGFBP-1 (P < 0.5) levels compared to overweight and obese patients.
  
  
  CONCLUSIONS
  Patients with IGF-IR blockade in combination with ADT demonstrated significant changes in IGF and glucose homeostasis pathway factors compared to patients receiving ADT alone. In the patients receiving combination therapy, patients with normal BMI had serum levels of glucose homeostasis components similar to individuals in the ADT-alone cohort, whereas patients with overweight and obese BMIs had serum levels that differed from the ADT cohort.
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Dean
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Sprenger
authors.forename: Junxiang
authors.initials: J
authors.lastname: Wan
authors.forename: Kathleen
authors.initials: K
authors.lastname: Haugk
authors.forename: William J
authors.initials: WJ
authors.lastname: Ellis
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lin
authors.forename: John M
authors.initials: JM
authors.lastname: Corman
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Dalkin
authors.forename: Elahe
authors.initials: E
authors.lastname: Mostaghel
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Pinchas
authors.initials: P
authors.lastname: Cohen
authors.forename: Bruce
authors.initials: B
authors.lastname: Montgomery
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control / Q000601:surgery; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000813:Anilides / Q000008:administration & dosage / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D015992:Body Mass Index; D015331:Cohort Studies; D017273:Goserelin / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D008297:Male; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use; D009765:Obesity / Q000150:complications*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control / Q000601:surgery; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012306:Risk; D055502:Secondary Prevention; D013002:Somatomedins / Q000032:analysis; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D014481:United States / Q000453:epidemiology
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C032231:IGFBP1 protein, human; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D009570:Nitriles; D013002:Somatomedins; D014105:Tosyl Compounds; D017273:Goserelin; C557414:cixutumumab; C053541:bicalutamide; D017526:Receptor, IGF Type 1