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Results: 1 to 10 of 19

Publication Record


A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.
Laubach JP, Moslehi JJ, Francis SA, San Miguel JF, Sonneveld P, Orlowski RZ, Moreau P, Rosiñol L, Faber EA, Voorhees P, Mateos MV, Marquez L, Feng H, Desai A, van de Velde H, Elliott J, Shi H, Dow E, Jobanputra N, Esseltine DL, Niculescu L, Anderson KC, Lonial S, Richardson PG
(2017) Br J Haematol 178: 547-560
MeSH Terms: Antineoplastic Agents, Benchmarking, Bortezomib, Cardiovascular Diseases, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Dyspnea, Heart Failure, Humans, Multiple Myeloma, Proteasome Inhibitors, Retrospective Studies, Risk Factors
Show Abstract · Added December 2, 2017
This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.
© 2017 John Wiley & Sons Ltd.
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13 MeSH Terms
Bortezomib augments lymphocyte stimulatory cytokine signaling in the tumor microenvironment to sustain CD8+T cell antitumor function.
Pellom ST, Dudimah DF, Thounaojam MC, Uzhachenko RV, Singhal A, Richmond A, Shanker A
(2017) Oncotarget 8: 8604-8621
MeSH Terms: Adenocarcinoma, Animals, Antineoplastic Agents, Bortezomib, Breast Neoplasms, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Cytokines, Female, Fibrosarcoma, Kidney Neoplasms, Lung Neoplasms, Lymphocytes, Tumor-Infiltrating, Mice, Inbred BALB C, Mice, Transgenic, Phosphatidylinositol 3-Kinase, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Proto-Oncogene Proteins c-akt, Receptors, Cytokine, STAT5 Transcription Factor, Signal Transduction, Tumor Escape, Tumor Microenvironment
Show Abstract · Added March 14, 2017
Tumor-induced immune tolerance poses a major challenge for therapeutic interventions aimed to manage cancer. We explored approaches to overcome T-cell suppression in murine breast and kidney adenocarcinomas, and lung fibrosarcoma expressing immunogenic antigens. We observed that treatment with a reversible proteasome inhibitor bortezomib (1 mg/kg body weight) in tumor-bearing mice significantly enhanced the expression of lymphocyte-stimulatory cytokines IL-2, IL-12, and IL-15. Notably, bortezomib administration reduced pulmonary nodules of mammary adenocarcinoma 4T1.2 expressing hemagglutinin (HA) model antigen (4T1HA) in mice. Neutralization of IL-12 and IL-15 cytokines with a regimen of blocking antibodies pre- and post-adoptive transfer of low-avidity HA518-526-specific CD8+T-cells following intravenous injection of 4T1HA cells increased the number of pulmonary tumor nodules. This neutralization effect was counteracted by the tumor metastasis-suppressing action of bortezomib treatments. In bortezomib-treated 4T1HA tumor-bearing mice, CD4+T-cells showed increased IL-2 production, CD11c+ dendritic cells showed increased IL-12 and IL-15 production, and HA-specific activated CD8+T-cells showed enhanced expression of IFNγ, granzyme-B and transcription factor eomesodermin. We also noted a trend of increased expression of IL-2, IL-12 and IL-15 receptors as well as increased phosphorylation of STAT5 in tumor-infiltrating CD8+T-cells following bortezomib treatment. Furthermore, bortezomib-treated CD8+T-cells showed increased phosphorylation of mitogen-activated protein kinase p38, and Akt, which was abrogated by phosphatidylinositide 3-kinase (PI3K) inhibitor. These data support the therapeutic potential of bortezomib in conjunction with other immunotherapies to augment the strength of convergent signals from CD8+T-cell signaling molecules including TCR, cytokine receptors and downstream PI3K/Akt/STAT5 pathways to sustain CD8+T-cell effector function in the tumor microenvironment.
2 Communities
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24 MeSH Terms
Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease.
Nyman JS, Merkel AR, Uppuganti S, Nayak B, Rowland B, Makowski AJ, Oyajobi BO, Sterling JA
(2016) Bone 91: 81-91
MeSH Terms: Animals, Bone Diseases, Bone and Bones, Bortezomib, Cancellous Bone, Cell Count, Cell Line, Tumor, Disease Models, Animal, Drug Therapy, Combination, Mice, Inbred C57BL, Multiple Myeloma, Osteoblasts, Receptors, Transforming Growth Factor beta, Signal Transduction, Transforming Growth Factor beta, Tumor Burden
Show Abstract · Added July 18, 2016
Multiple myeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2-/-) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease.
Published by Elsevier Inc.
2 Communities
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16 MeSH Terms
Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer.
McLoed AG, Sherrill TP, Cheng DS, Han W, Saxon JA, Gleaves LA, Wu P, Polosukhin VV, Karin M, Yull FE, Stathopoulos GT, Georgoulias V, Zaynagetdinov R, Blackwell TS
(2016) Cell Rep 16: 120-132
MeSH Terms: Animals, Bortezomib, Carcinogenesis, Carcinoma, Non-Small-Cell Lung, Cell Proliferation, Epithelial Cells, Humans, I-kappa B Kinase, Interleukin-1beta, Lung Neoplasms, Mice, Myeloid Cells, NF-kappa B, Neutrophils, Signal Transduction, Survival Analysis
Show Abstract · Added March 29, 2017
Although epithelial NF-κB signaling is important for lung carcinogenesis, NF-κB inhibitors are ineffective for cancer treatment. To explain this paradox, we studied mice with genetic deletion of IKKβ in myeloid cells and found enhanced tumorigenesis in Kras(G12D) and urethane models of lung cancer. Myeloid-specific inhibition of NF-κB augmented pro-IL-1β processing by cathepsin G in neutrophils, leading to increased IL-1β and enhanced epithelial cell proliferation. Combined treatment with bortezomib, a proteasome inhibitor that blocks NF-κB activation, and IL-1 receptor antagonist reduced tumor formation and growth in vivo. In lung cancer patients, plasma IL-1β levels correlated with poor prognosis, and IL-1β increased following bortezomib treatment. Together, our studies elucidate an important role for neutrophils and IL-1β in lung carcinogenesis and resistance to NF-κB inhibitors.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
2 Communities
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16 MeSH Terms
Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression.
Jin R, Yamashita H, Yu X, Wang J, Franco OE, Wang Y, Hayward SW, Matusik RJ
(2015) Oncogene 34: 3700-10
MeSH Terms: Androgen Antagonists, Anilides, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Boronic Acids, Bortezomib, Cell Line, Tumor, Humans, Male, NF-kappa B, Nitriles, Prostatic Neoplasms, Castration-Resistant, Pyrazines, Receptors, Androgen, Signal Transduction, Tosyl Compounds, Xenograft Model Antitumor Assays
Show Abstract · Added January 20, 2015
Androgen receptor splicing variants (ARVs) that lack the ligand-binding domain (LBD) are associated with the development of castration-resistant prostate cancer (CRPC), including resistance to the new generation of high-affinity anti-androgens. However, the mechanism by which ARV expression is regulated is not fully understood. In this study, we show that the activation of classical nuclear factor-kappa B (NF-κB) signaling increases the expression of ARVs in prostate cancer (PCa) cells and converts androgen-sensitive PCa cells to become androgen-insensitive, whereas downregulation of NF-κB signaling inhibits ARV expression and restores responsiveness of CRPC to anti-androgen therapy. In addition, we demonstrated that combination of anti-androgen with NF-κB-targeted therapy inhibits efficiently tumor growth of human CRPC xenografts. These results indicate that induction of ARVs by activated NF-κB signaling in PCa cells is a critical mechanism by which the PCa progresses to CRPC. This has important implications as it can prolong the survival of CRPC patients by restoring the tumors to once again respond to conventional androgen-deprivation therapy (ADT).
1 Communities
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17 MeSH Terms
Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group.
Ciombor KK, Feng Y, Benson AB, Su Y, Horton L, Short SP, Kauh JS, Staley C, Mulcahy M, Powell M, Amiri KI, Richmond A, Berlin J
(2014) Invest New Drugs 32: 1017-27
MeSH Terms: Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Boronic Acids, Bortezomib, Carcinoma, Hepatocellular, Chemokine CCL5, Cytokines, Disease-Free Survival, Doxorubicin, Female, Humans, Liver Neoplasms, Male, Middle Aged, Pyrazines, Treatment Outcome, Vascular Endothelial Growth Factor A, Young Adult
Show Abstract · Added August 7, 2014
PURPOSE - To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival.
EXPERIMENTAL DESIGN - This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m(2) IV on d1, 4, 8, 11) and doxorubicin (15 mg/m(2) IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate.
RESULTS - Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1 months. The most common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1α and EMSA for NF-κB at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1α/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment.
CONCLUSIONS - The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious.
2 Communities
2 Members
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19 MeSH Terms
Preventing the autophagic survival response by inhibition of calpain enhances the cytotoxic activity of bortezomib in vitro and in vivo.
Escalante AM, McGrath RT, Karolak MR, Dorr RT, Lynch RM, Landowski TH
(2013) Cancer Chemother Pharmacol 71: 1567-76
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Autophagy, Boronic Acids, Bortezomib, Calpain, Cell Line, Tumor, Cell Survival, Drug Synergism, HIV Protease Inhibitors, Humans, Mice, Mice, SCID, Multiple Myeloma, Nelfinavir, Pyrazines, RNA, Small Interfering, Xenograft Model Antitumor Assays
Show Abstract · Added August 19, 2013
PURPOSE - Bortezomib, a first-generation proteasome inhibitor, induces an endoplasmic reticulum (ER) stress response, which ultimately leads to dysregulation of intracellular Ca(2+) and apoptotic cell death. This study investigated the role of the Ca(2+)-dependent enzyme, calpain, in bortezomib cytotoxicity. A novel therapeutic combination was evaluated in which HIV protease inhibitors were used to block calpain activity and enhance bortezomib cytotoxicity in myeloma cells in vitro and in vivo.
METHODS - Bortezomib-mediated cell death was examined using assays for apoptosis (Annexin V staining), total cell death (trypan blue exclusion), and growth inhibition (MTT). The effects of calpain on bortezomib-induced cytotoxicity were investigated using siRNA knockdown or pharmaceutical inhibitors. Enzyme activity assays and immunofluorescence analysis were used to identify mechanistic effects.
RESULTS - Inhibition of the Ca(2+)-dependent cysteine protease calpain, either by pharmacologic or genetic means, enhances or accelerates bortezomib-induced myeloma cell death. The increase in cell death is not associated with an increase in caspase activity, nor is there evidence of greater inhibition of proteasome activity, suggesting an alternate, calpain-regulated mechanism of bortezomib-induced cell death. Bortezomib initiates an autophagic response in myeloma cells associated with cell survival. Inhibition of calpain subverts the cytoprotective function of autophagy leading to increased bortezomib-mediated cell death. Combination therapy with bortezomib and the calpain-blocking HIV protease inhibitor, nelfinavir, reversed bortezomib resistance and induced near-complete tumor regressions in an SCID mouse xenograft model of myeloma.
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19 MeSH Terms
Phase II 2-arm trial of the proteasome inhibitor, PS-341 (bortezomib) in combination with irinotecan or PS-341 alone followed by the addition of irinotecan at time of progression in patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck (E1304): a trial of the Eastern Cooperative Oncology Group.
Gilbert J, Lee JW, Argiris A, Haigentz M, Feldman LE, Jang M, Arun P, Van Waes C, Forastiere AA
(2013) Head Neck 35: 942-8
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Boronic Acids, Bortezomib, Camptothecin, Carcinoma, Squamous Cell, Cytokines, Disease Progression, Female, Head and Neck Neoplasms, Humans, Irinotecan, Male, Middle Aged, NF-kappa B, Pyrazines, Squamous Cell Carcinoma of Head and Neck, Treatment Outcome
Show Abstract · Added March 5, 2014
BACKGROUND - Constitutive activation of nuclear factor κB (NF-κB) is associated with poor prognosis. Irinotecan demonstrates single-agent activity in head and neck cancer but activates NF-κB, promoting cell survival and resistance. Bortezomib is a proteasome inhibitor that inactivates NF-κB.
PATIENTS AND METHODS - We performed a randomized phase II trial of bortezomib on days 1, 4, 8, and 11 and irinotecan on days 1 and 8 of each 21-day cycle or single-agent bortezomib on days 1, 4, 8, and 11 on a 21-day cycle. The addition of irinotecan to bortezomib was allowed in patients who progressed on bortezomib alone.
RESULTS - The response rate of bortezomib and irinotecan was 13%. One patient had a partial response to bortezomib alone (response rate 3%). No responses were seen in patients with addition of irinotecan at time of progression on bortezomib.
CONCLUSIONS - The bortezomib-based regimens evaluated in this study have minimal activity in recurrent or metastatic head and neck cancer.
Published 2012 Wiley Periodicals, Inc.
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20 MeSH Terms
Opposing effects of bortezomib-induced nuclear factor-κB inhibition on chemical lung carcinogenesis.
Karabela SP, Psallidas I, Sherrill TP, Kairi CA, Zaynagetdinov R, Cheng DS, Vassiliou S, McMahon F, Gleaves LA, Han W, Stathopoulos I, Zakynthinos SG, Yull FE, Roussos C, Kalomenidis I, Blackwell TS, Stathopoulos GT
(2012) Carcinogenesis 33: 859-67
MeSH Terms: Animals, Antineoplastic Agents, Boronic Acids, Bortezomib, Cell Line, Cell Line, Tumor, Humans, Lung Neoplasms, Mice, Mice, Inbred BALB C, NF-kappa B, Pyrazines
Show Abstract · Added February 26, 2013
Since recent evidence indicates a requirement for epithelial nuclear factor (NF)-κB signaling in lung tumorigenesis, we investigated the impact of the NF-κB inhibitor bortezomib on lung tumor promotion and growth. We used an experimental model in which wild-type mice or mice expressing an NF-κB reporter received intraperitoneal urethane (1 g/kg) followed by twice weekly bortezomib (1 mg/kg) during distinct periods of tumor initiation/progression. Mice were serially assessed for lung NF-κB activation, inflammation and carcinogenesis. Short-term proteasome inhibition with bortezomib did not impact tumor formation but retarded the growth of established lung tumors in mice via effects on cell proliferation. In contrast, long-term treatment with bortezomib resulted in significantly increased lung tumor number and size. This tumor-promoting effect of prolonged bortezomib treatment was associated with perpetuation of urethane-induced inflammation and chronic upregulation of interleukin-1β and proinflammatory C-X-C motif chemokine ligands (CXCL) 1 and 2 in the lungs. In addition to airway epithelium, bortezomib inhibited NF-κB in pulmonary macrophages in vivo, presenting a possible mechanism of tumor amplification. In this regard, RAW264.7 macrophages exposed to bortezomib showed increased expression of interleukin-1β, CXCL1 and CXCL2. In conclusion, although short-term bortezomib may exert some beneficial effects, prolonged NF-κB inhibition accelerates chemical lung carcinogenesis by perpetuating carcinogen-induced inflammation. Inhibition of NF-κB in pulmonary macrophages appears to play an important role in this adverse process.
1 Communities
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12 MeSH Terms
Consolidative therapy with stem cell transplantation improves survival of patients with mantle cell lymphoma after any induction regimen.
Reddy N, Greer JP, Goodman S, Kassim A, Morgan DS, Chinratanalab W, Brandt S, Englehardt B, Oluwole O, Jagasia MH, Savani BN
(2012) Exp Hematol 40: 359-66
MeSH Terms: Adult, Aged, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Combined Chemotherapy Protocols, Boronic Acids, Bortezomib, Consolidation Chemotherapy, Cyclophosphamide, Dexamethasone, Disease-Free Survival, Doxorubicin, Female, Humans, Kaplan-Meier Estimate, Lymphoma, Mantle-Cell, Male, Middle Aged, Peripheral Blood Stem Cell Transplantation, Prednisone, Pyrazines, Remission Induction, Retrospective Studies, Rituximab, Transplantation Conditioning, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Vincristine
Show Abstract · Added March 5, 2014
Intensive induction regimen followed by high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) is frequently used to improve outcomes in patients with mantle-cell lymphoma. The comparative impact of conventional vs intensive induction regimen before transplantation is unknown. Forty-eight patients with mantle-cell lymphoma receiving SCT at our institution between January 2000 and December 2010 were included in this study. At the time of initial presentation, 43 (89.5%) had stage IV disease and 18 (37.5%) received more than one chemotherapy regimen before transplantation. Forty patients underwent auto-SCT and 7 had allogeneic SCT (allo-SCT); 1 patient had an allo-SCT for relapsed disease after auto-SCT. At the time of this analysis (median follow-up of 6 years from diagnosis and 4 years from transplantation), 40 patients (88%) were alive with a 5-year disease-free survival of 74.8%. Age, disease stage, number of regimens pre-SCT, pre-SCT disease status, and type of SCT had no impact on long-term outcomes. Importantly, there were no differences among the types of induction regimen on outcomes in this cohort receiving SCT. Based on our data, we believe that future studies should focus on strategies to prevent disease relapse rather than comparing induction regimens before stem cell transplantation.
Copyright © 2012 ISEH - Society for Hematology and Stem Cells. All rights reserved.
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28 MeSH Terms