title: A phase II trial with pharmacodynamic endpoints of the proteasome inhibitor bortezomib in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  To evaluate the effects of the proteasome inhibitor bortezomib on tumor growth in patients with advanced colorectal cancer, and to explore the relationship between correlative studies and clinical outcome.
  
  
  METHODS
  Bortezomib (1.3 mg/m(2)) was administered i.v. on days 1, 4, 8, and 11 of a 21-day cycle. Tumor response was assessed after every two cycles. Tumor biopsies were done prior to treatment and on day 9 of the first treatment cycle. Biopsies were examined for Ser(32/36)-IkappaB, Ser(276)-nuclear factor kappaB (NFkappaB), hypoxia-inducible factor-1alpha (HIF-1alpha), carbonic anhydrase IX (CAIX), p53, and microvessel density using immunohistochemistry.
  
  
  RESULTS
  Nineteen patients received 42 cycles (range 1-4) of bortezomib. No objective response was seen; three patients had stable disease at cycle 2, two patients had progressive disease after cycle 1, and 11 patients had progressive disease at cycle 2. Of the three patients with stable disease, one had progressive disease after cycle 4, and two were withdrawn due to toxicity. The median time to progression was 5.1 weeks (95% confidence interval, 5.1-11.1 weeks). There was a significant increase in the expression of HIF-1alpha relative to its transcriptional target CAIX following bortezomib, and a similar effect was also observed in a companion study using a human tumor xenograft model. Expression of p53, Ser(276)-NFkappaB, and Ser(32/36)-IkappaB was unchanged.
  
  
  CONCLUSIONS
  Single agent bortezomib is inactive in metastatic colorectal cancer. Using this regimen, there was no detectable effect on NFkappaB, but a significant accumulation of HIF-1alpha was seen relative to CAIX. This suggests that proteasome inhibition alters the response to tumor hypoxia, and further investigation of this effect is indicated.
authors.affiliation: Princess Margaret Phase II Consortium, Toronto, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: Mackay
authors.forename: David
authors.initials: D
authors.lastname: Hedley
authors.forename: Pierre
authors.initials: P
authors.lastname: Major
authors.forename: Carol
authors.initials: C
authors.lastname: Townsley
authors.forename: Mary
authors.initials: M
authors.lastname: Mackenzie
authors.forename: Mark
authors.initials: M
authors.lastname: Vincent
authors.forename: Pam
authors.initials: P
authors.lastname: Degendorfer
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Trudey
authors.initials: T
authors.lastname: Nicklee
authors.forename: Diana
authors.initials: D
authors.lastname: Birle
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Lillian
authors.initials: L
authors.lastname: Siu
authors.forename: Malcolm
authors.initials: M
authors.lastname: Moore
authors.forename: Amit
authors.initials: A
authors.lastname: Oza
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001706:Biopsy; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008099:Liver / Q000473:pathology; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D012694:Serine / Q000737:chemistry; D013997:Time Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; D012694:Serine; D000069286:Bortezomib; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases