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5526.Full.Pdf Cancer Therapy: Clinical A Phase II Trial with Pharmacodynamic Endpoints of the Proteasome Inhibitor Bortezomib in Patients with Metastatic Colorectal Cancer Helen Mackay,1David Hedley,1Pierre Major,1CarolTownsley,1Mary Mackenzie,1MarkVincent,1 Pam Degendorfer,1Ming-Sound Tsao,1Trudey Nicklee,1Diana Birle,1John Wright,2 Lillian Siu,1Malcolm Moore,1and Amit Oza1 Abstract Purpose: 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. Design: Bortezomib (1.3 mg/m2) was administered i.v. on days 1, 4, 8, and 11of a 21-day cycle. Tumor response was assessed after every two cycles. Tumor biopsies were done prior to treat- ment and on day 9 of the first treatment cycle. Biopsies were examined for Ser32/36-InB, Ser276- nuclear factor nB(NFnB), hypoxia-inducible factor-1a (HIF-1a), 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 cycle1,and11patients 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 Of the three patients with stable disease, one had progressive disease after cycle 4, and two were withdrawn due to toxicity.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 5.1weeks (95% confidence interval, 5.1-11.1weeks).There was a signifi- cant increase in the expression of HIF-1arelative to its transcriptional target CAIX following borte- zomib, and a similar effect was also observed in a companion study using a human tumor xenograft model. Expression of p53, Ser276-NFnB, and Ser32/36-InB was unchanged. Conclusion: Single agent bortezomib is inactive in metastatic colorectal cancer. Using this regi- men, there was no detectable effect on NFnB,butasignificantaccumulationofHIF-1awas seen relative to CAIX. This suggests that proteasome inhibition alters the response to tumor hypoxia, and further investigation of this effect is indicated. Despite the introduction of regimens incorporating the newer proteasome results in stabilization of InB, enhanced apoptosis agents irinotecan and oxaliplatin, the median survival for and down-regulation of factors related to cancer progression patients with metastatic colorectal cancer remains <20 months. and metastasis (5, 6). In contrast, HIF-1, which plays a major The poor outlook for these patients warrants the investigation role in promoting cell survival under conditions of tumor of new agents with novel mechanisms of action (1). hypoxia, is inactivated under aerobic conditions by proteaso- The ubiquitin-proteasome proteolytic pathway regulates the mal degradation of the HIF-1a subunit. Therefore, proteasomal metabolism of key proteins including cyclins, p21, and p27 inhibition might favor survival by accumulation of HIF-1, required for cell cycle progression (2). In addition, the although in vitro data suggests that under these conditions, HIF- proteasome regulates major transcription factors, such as p53, 1a may be transcriptionally inactive (7). nuclear factor-nB (NFnB) and hypoxia-inducible factor-1 (HIF- Targeting the proteasome has recently emerged as a novel 1). NFnB is activated by proteasome-mediated degradation of approach to cancer therapy (8). Bortezomib (formerly known the inhibitory protein InB (3). Activated NFnB promotes cell as PS-341), a dipeptidyl boronic acid, is a specific and highly survival, angiogenesis, and metastasis by inducing expression of selective inhibitor of the 26S proteasome. In preclinical studies, pro-survival proteins (bcl2), cell adhesion molecules, and bortezomib shows significant and wide-ranging antitumor growth factors (interleukin-6; refs. 4, 5). Inhibition of the activity (8). I.v. administration of bortezomib to tumor-bearing mice results in significant regression in two human colon (LoVo and HT-29) cancer xenograft models (8, 9). A phase II Authors’ Affiliations: 1Princess Margaret Phase II Consortium,Toronto, Canada, trial of bortezomib in patients with metastatic colorectal cancer 2 and National Cancer Institute, Rockville, Maryland is therefore appropriate. Investigation of the biological effects Received 1/12/05; revised 3/24/05; accepted 5/6/05. The costs of publication of this article were defrayed in part by the payment of page of novel agents within tumor tissue is vital to understanding charges. This article must therefore be hereby marked advertisement in accordance mechanisms of drug action at the molecular level. Therefore, in with 18 U.S.C. Section 1734 solely to indicate this fact. addition to the primary aims of determining the efficacy and Requests for reprints: Amit Oza, Princess Margaret Hospital, University Health toxicity in patients with advanced colorectal cancer, we Network, Department of Medical Oncology and Hematology, 610 University investigated the pharmacodynamic effects using core biopsies Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2818; Fax: 416- 946-2082; E-mail: [email protected]. obtained from liver metastases pretreatment and after 9 days of F 2005 American Association for Cancer Research. treatment with bortezomib. Whereas we found no consistent Clin Cancer Res 2005;11(15) August 1, 2005 5526 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2005 American Association for Cancer Research. Bortezomid in Patients with Metastatic Colorectal Cancer effects on p53 or NFnB expression, differential effects on HIF- phospho-NFnB(Ser276) 1:50 dilution overnight, both from Cell 1a and the HIF-1 transcriptional target carbonic anhydrase IX Signaling Technology (Beverly MA); p53 (Dako DO7, Glostrup, (CAIX) indicated a significant disruption of the tumor response Denmark) 1:100 dilution overnight; HIF-1a (BD Transduction Labs, to hypoxia following treatment with bortezomib. This effect Lexington, KY) 1:50 dilution overnight; CAIX (a gift from Dr. Adrian Harris, University of Oxford, United Kingdom) 1:200 dilution over- was also seen in a companion study using a human tumor night; and CD34 (Novocastra QBend10, Newcastle-upon-Tyne, United xenograft model of hypoxia, suggesting that proteasome Kingdom) 1:80 dilution for 1 hour. The slides were then developed for inhibitors should be further tested for their ability to target immunohistochemistry using appropriate secondary antibodies and hypoxic tumor tissue. a standard streptavidin/biotin-immunoperoxidase method, with NovaRed (Vector Laboratories, Burlingham, CA) as the chromogen Materials and Methods and hematoxylin as the counterstain. The immunohistochemically stained sections, and an additional This was an open-label, nonrandomized multicenter phase II study section stained with H&E, were first examined by the study pathologist by the Princess Margaret Hospital Phase II Consortium. The study was (M-S. Tsao). Areas of viable tumor tissue within the cores were approved by the Local Research Ethics Committee at each of the identified, the extent of antibody staining assessed descriptively, and in participating institutions. consultation with D. Hedley and T. Nicklee, appropriate protocols for Patients. All patients entered into this study had histologically or digital image capture and analysis were determined. Serial sections cytologically confirmed recurrent or metastatic colorectal adenocarci- labeled for HIF-1a, CAIX, and CD34 were imaged at 10Â objective, and noma. Eligibility criteria included: life expectancy z12 weeks; Eastern composite, tiled-field images of the entire section obtained using a Cooperative Oncology Group performance status V1, adequate scanning autostage as previously described (10). The images of hematologic (absolute neutrophil count z2 Â 109 LÀ1; platelets phospho-NFnB staining were obtained by blue laser light absorption, z100 Â 109 LÀ1), hepatic (bilirubin V1.25Â upper limit of normal; using a laser scanning system (TISSUEscope, Biomedical Photometrics, aspartate aminotransferase/alanine aminotransferase V5Â upper limit Waterloo, ON). The laser spot size used gave a pixel resolution of f2 of normal) and renal function (serum creatinine V1.25Â upper limit of Am. Image analysis was done using MCID Elite software (Imaging normal) with at least one site of measurable disease (z1 cm in at least Research, St. Catharines, ON). one dimension with spiral computed tomography scan). Patients had Statistical methods. Summary statistics, such as the mean, median, received V1 prior line of chemotherapy for metastatic disease. This range and, proportion were used to describe the patient sample. Overall could include 5-fluorouracil, irinotecan and/or oxaliplatin (or 5- and progression-free survival estimates were computed using the fluorouracil followed by irinotecan or oxaliplatin). Irradiation was Kaplan-Meier method. Survival times were taken from the day the allowed provided it was completed >4 weeks before study entry. patient first received therapy until death or last known follow-up date Patients were excluded if they had zgrade 1 neuropathy. In cases where for overall survival, and until death, date of progression, or last known there was a medical contraindication to tumor biopsy, study entry was follow-up date for progression-free survival. at the discretion of the principal investigator. Written informed consent HIF-1/CAIX ratio was calculated by summing the HIF-1 value for all was obtained from all patients prior to starting treatment. sections
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