Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody

Anil Shanker, Alan David Brooks, Carlos Alberto Tristan, John William Wine, Peter John Elliott, Hideo Yagita, Kazuyoshi Takeda, Mark John Smyth, William J Murphy, Thomas Joseph Sayers

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)649-662
Number of pages14
JournalJournal of the National Cancer Institute
Volume100
Issue number9
DOIs
StatePublished - May 2008
Externally publishedYes

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Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Antibodies
Neoplasms
Confidence Intervals
Caspase 8
Mitochondrial Membranes
Neoplasm Metastasis
Caspase 3
Cell Death
Monoclonal Antibodies
Bortezomib
TNF-Related Apoptosis-Inducing Ligand Receptors
Lung
Proteasome Inhibitors
Hematology
Cell Count
Breast Neoplasms
Carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody. / Shanker, Anil; Brooks, Alan David; Tristan, Carlos Alberto; Wine, John William; Elliott, Peter John; Yagita, Hideo; Takeda, Kazuyoshi; Smyth, Mark John; Murphy, William J; Sayers, Thomas Joseph.

In: Journal of the National Cancer Institute, Vol. 100, No. 9, 05.2008, p. 649-662.

Research output: Contribution to journalArticle

Shanker, Anil ; Brooks, Alan David ; Tristan, Carlos Alberto ; Wine, John William ; Elliott, Peter John ; Yagita, Hideo ; Takeda, Kazuyoshi ; Smyth, Mark John ; Murphy, William J ; Sayers, Thomas Joseph. / Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody. In: Journal of the National Cancer Institute. 2008 ; Vol. 100, No. 9. pp. 649-662.
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abstract = "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.",
author = "Anil Shanker and Brooks, {Alan David} and Tristan, {Carlos Alberto} and Wine, {John William} and Elliott, {Peter John} and Hideo Yagita and Kazuyoshi Takeda and Smyth, {Mark John} and Murphy, {William J} and Sayers, {Thomas Joseph}",
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TY - JOUR

T1 - Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody

AU - Shanker, Anil

AU - Brooks, Alan David

AU - Tristan, Carlos Alberto

AU - Wine, John William

AU - Elliott, Peter John

AU - Yagita, Hideo

AU - Takeda, Kazuyoshi

AU - Smyth, Mark John

AU - Murphy, William J

AU - Sayers, Thomas Joseph

PY - 2008/5

Y1 - 2008/5

N2 - 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.

AB - 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.

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