A Phase II Trial with Pharmacodynamic Endpoints of the Proteasome Inhibitor Bortezomib in Patients with Metastatic Colorectal Cancer

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Abstract
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. 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. 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 Of the three patients with stable disease, one had progressive disease after cycle 4, and two were withdrawn due to toxicity.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. 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.

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