Journal of the National Cancer Institute Advance Access originally published online on April 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(9):649-662; doi:10.1093/jnci/djn113
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Published by Oxford University Press 2008.
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Treating Metastatic Solid Tumors With Bortezomib and a Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor Agonist Antibody
Affiliations of authors: Laboratory of Experimental Immunology, Cancer and Inflammation Program, SAIC–Frederick, Inc, National Cancer Institute–Frederick, Frederick, MD (AS, ADB, CAT, JWW, TJS); Sirtris Pharmaceuticals Inc, Cambridge, MA (PJE); Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan (HY, KT); Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia (MJS); Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV (WJM)
Correspondence to: Thomas J. Sayers, Laboratory of Experimental Immunology, Cancer and Inflammation Program, SAIC–Frederick, Inc, National Cancer Institute–Frederick, Frederick, MD 21702 (e-mail: sayerst{at}mail.nih.gov).
Background: Resistance of tumors to cell death signals poses a complex clinical problem. We explored the therapeutic potential and in vivo toxicity of a combination of bortezomib, a proteasome inhibitor, and MD5-1, a tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor (DR5) agonist monoclonal antibody, in mouse carcinomas.
Methods: Mice bearing Renca-FLAG (renal) or 4T1 (mammary) tumors were treated with bortezomib and/or MD5-1 and examined for lung metastases (Renca-FLAG: n = 93; 4T1: n = 40) or monitored for survival (Renca-FLAG: n = 143). Toxicity was assessed by histopathology and hematology. Viability and apoptotic signaling in Renca-FLAG and 4T1 cells treated with bortezomib alone or in combination with TRAIL were analyzed using 3-[4,5-dimethyiazol-2-yl-5]-[3-carboxymethyloxyphenyl]-2-[4-sulfophenyl]-2H tetrazolium assay and by measuring mitochondrial membrane depolarization and caspase-8 and caspase-3 activation. All statistical tests were two-sided.
Results: Bortezomib (20 nM) sensitized Renca-FLAG and 4T1 cells to TRAIL-mediated apoptosis (mean percent decrease in numbers of viable cells, bortezomib + TRAIL vs TRAIL: Renca-FLAG, 95% vs 34%, difference = 61%, 95% confidence interval [CI] = 52% to 69%, P < .001; 4T1, 85% vs 20%, difference = 65%, 95% CI = 62% to 69%, P < .001). Sensitization involved activation of caspase-8 and caspase-3 but not mitochondrial membrane depolarization, suggesting an amplified signaling of the extrinsic cell death pathway. Treatment with bortezomib and MD5-1 reduced lung metastases in mice carrying Renca and 4T1 tumors (mean number of metastases, bortezomib + MD5-1 vs MD5-1: Renca-FLAG, 1 vs 8, difference = 7, 95% CI = 5 to 9, P < .001; 4T1, 1 vs 12, difference = 11, 95% CI = 9 to 12, P < .001) and increased median survival of mice bearing Renca-FLAG tumors (bortezomib + MD5-1 vs bortezomib + control isotype antibody: 22 of 30 [73%] were still alive at day 180 vs median survival of 42 days [95% CI = 41 to 44 days, P < .001]) in the absence of obvious toxicity.
Conclusion: Bortezomib combined with DR5 agonist monoclonal antibody may be a useful treatment for metastatic solid tumors.
| CONTEXT AND CAVEATS Prior knowledge Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is involved in host immunosurveillance against tumor development and metastasis and been shown to have antitumor activity in various mouse models of human cancers. Bortezomib is an inhibitor of protein degradation and has been approved by the Food and Drug Administration for the treatment of multiple myeloma. Study design Cell viability and signaling of apoptotic death of mouse renal adenocarcinoma and mammary carcinoma cells were assayed after treatment with TRAIL and/or bortezomib. Development of lung metastases and survival of mice carrying tumors derived from these cells were measured after treatment with bortezomib and/or MD5-1, a TRAIL receptor agonist antibody. Contributions More cells underwent apoptotic death after treatment with bortezomib and TRAIL than with TRAIL alone. Mice treated with bortezomib and MD5-1 lived longer and developed fewer lung metastases than mice treated with MD5-1 alone. Implications The combination of bortezomib and a TRAIL agonist antibody may be useful in the treatment of solid metastatic tumors. Limitations It is unknown whether results will be similar in humans or what nonspecific toxic effects a similar drug combination might have in humans.
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Manuscript received September 5, 2007; revised February 15, 2008; accepted March 17, 2008.
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