Bortezomib (VELCADE®) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits

Yang, Changqing; González-Angulo, Ana M.; Reuben, James M.; Booser, Daniel J.; Pusztai, Lajos; Krishnamurthy, Savitri; Esseltine, Dixie Lee; Stec, James; Broglio, Kristine; Islam, Rabiul; Hortobágyi, Gabriel N.; Cristofanilli, Massimo

doi:10.1093/annonc/mdj131

Cited by 126 publications

(103 citation statements)

References 17 publications

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“…It is the first of a novel class of anticancer drugs, known as proteasome inhibitors, to be approved for clinical use. Since its discovery, bortezomib has been used to treat a variety of human tumors, such as multiple myeloma (3)(4)(5)(6)(7)(8), lymphoma (9,10), non-small cell lung cancer (11,12), renal cancer (13,14), prostate cancer (15)(16)(17), pancreatic cancer (18), melanoma (19), breast cancer (20,21), and ovarian cancer (22). Bortezomib inhibits a key regulator of intracellular protein degradation, the 26S proteasome, which has the downstream effect of inducing apoptotic cancer cell death by means of multiple mechanisms.…”

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confidence: 99%

Immune Mechanism of the Antitumor Effects Generated by Bortezomib

Chang

Hsu

et al. 2012

The Journal of Immunology

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Bortezomib, a proteasome inhibitor, is a chemotherapeutic drug that is commonly used to treat a variety of human cancers. The antitumor effects of bortezomib-induced tumor cell immunogenicity have not been fully delineated. In this study, we examined the generation of immune-mediated antitumor effects in response to treatment by bortezomib in a murine ovarian tumor model. We observed that tumor-bearing mice that were treated with bortezomib had CD8+ T cell-mediated inhibition of tumor growth. Furthermore, the comparison of tumor cell-based vaccines that were produced from tumor cells treated or untreated with bortezomib showed vaccination with drug-treated tumor cell-based vaccines elicited potent tumor-specific CD8+ T cell immune response with improved therapeutic antitumor effect in tumor-bearing mice. Conversely, the untreated tumor cell-based vaccines led to no appreciable antitumor response. Treatment of tumor cells with bortezomib led to the upregulation of Hsp60 and Hsp90 on the cell surface and promoted their phagocytosis by dendritic cells (DCs). However, cell surface expression of Hsp60, instead of Hsp90, is the more important determinant of whether bortezomib-treated tumor cells can generate tumor-specific CD8+ T cells. CD11c+ DCs that were treated with bortezomib in vitro had enhanced phagocytic activities. In addition, CD11c+ DCs from bortezomib-treated tumor-bearing mice had increased maturation. At lower concentrations, bortezomib had no inhibitory effects on T cell proliferation. Taken together, our data indicate that bortezomib can render tumor cells immunogenic by upregulating the cell surface expression of heat shock protein 60 and heat shock protein 90, as well as improve DC function, which results in potent immune-mediated antitumor effects.

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confidence: 99%

Immune Mechanism of the Antitumor Effects Generated by Bortezomib

Chang

Hsu

et al. 2012

The Journal of Immunology

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“…Two previous phase II studies with single agent bortezomib in metastatic breast cancer have only reported disease stabilisation. Yang et al (32) reported on a phase II study with bortezomib using a biweekly regimen of 1.5 mg/m 2 followed by one week rest every 21 days in 12 patients, all suffering from measurable metastatic breast cancer. One (8.3%) of these 12 patients experienced stable disease for up to 5 cycles of 21 days.…”

Section: Discussionmentioning

confidence: 99%

A phase II study of the combination of endocrine treatment and bortezomib in patients with endocrine-resistant metastatic breast cancerA phase II study of the combination of endocrine treatment and bortezomib in patients with endocrine-resistant metastatic breast cancer

Dirix

2011

Oncol Rep

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“…Moreover, PS-341 exhibits a wide range of antitumor activity and increases the activity of multiple chemotherapeutic agents (5,6,22,23). Although PS-341 was found to be active against breast cancer cell lines, in vivo models and phase Ⅰ clinical trials have found it ineffective for breast cancer when used as a single agent (24), and limited efficacy of PS-341 has been noted in combination with several chemotherapeutic agents (25,26).…”

Section: Discussionmentioning

confidence: 99%

Proteasome inhibitor bortezomib (PS-341) enhances RANKL-induced MDA-MB-231 breast cancer cell migration

Liu¹

2011

Mol Med Report

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Abstract. The receptor activator of nuclear factor κB ligand/ receptor activator of nuclear factor κB (RANKL/RANK) pathway is crucial for the migration of RANK-expressing cancer cells. The ubiquitin-proteasome protein degradation pathway plays a significant role in tumor metastasis. However, the relationship between these two pathways in tumor cell migration is unclear. In the present study, we explored the effect of the proteasome inhibitor bortezomib (PS-341) on RANKL-induced MDA-MB-231 breast cancer cell migration. Transwell migration assay showed that RANKL-induced MDA-MB-231 cell migration was significantly blocked by the decoy receptor osteoprotegerin (OPG), and was also inhibited by the PI3-K inhibitor LY294002. Western blotting results showed that Akt was rapidly activated by soluble RANKL treatment. PS-341 significantly enhanced RANKL-induced MDA-MB-231 cell migration. Further study showed that the enhancement of migration by PS-341 involved upregulation of activated Akt and RANK. Our results for the first time support the theory that PS-341 treatment may be unsuitable for RANK-positive breast cancer patients.

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Bortezomib (VELCADE®) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits

Cited by 126 publications

References 17 publications

Immune Mechanism of the Antitumor Effects Generated by Bortezomib

Immune Mechanism of the Antitumor Effects Generated by Bortezomib

A phase II study of the combination of endocrine treatment and bortezomib in patients with endocrine-resistant metastatic breast cancerA phase II study of the combination of endocrine treatment and bortezomib in patients with endocrine-resistant metastatic breast cancer

Proteasome inhibitor bortezomib (PS-341) enhances RANKL-induced MDA-MB-231 breast cancer cell migration

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