A phase II trial with pharmacodynamic endpoints of the proteasome inhibitor bortezomib in patients with metastatic colorectal cancer.
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 Of the three patients with stable disease, one had progressive disease after cycle 4, and two were withdrawn due to toxicity.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.
Mackay
Helen
H
Princess Margaret Phase II Consortium, Toronto, Canada.
Hedley
David
D
Major
Pierre
P
Townsley
Carol
C
Mackenzie
Mary
M
Vincent
Mark
M
Degendorfer
Pam
P
Tsao
Ming-Sound
MS
Nicklee
Trudey
T
Birle
Diana
D
Wright
John
J
Siu
Lillian
L
Moore
Malcolm
M
Oza
Amit
A
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
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