Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for JAK/STAT pathway inhibition in myeloma patients

Oliveira, Mariana Bleker de; Fook-Alves, Veruska L.; Eugênio, Angela Isabel Pereira; Fernando, Rodrigo Carlini; Sanson, Luiz Felipe G.; Carvalho, M. F.; Braga, Walter Moisés Tobias; Davies, Faith E.; Colleoni, Gisele W. B.

doi:10.1016/j.canlet.2017.06.016

Cited by 33 publications

(30 citation statements)

References 27 publications

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“…Expression of phosphorylated STAT3 is associated with poor prognosis and survival in MM patients [115]. Several preclinical studies have demonstrated that inhibition of JAK/STAT3 signaling alone or in combination with other antitumor reagents inhibits MM cell growth both in vitro and in vivo [116][117][118][119].…”

Section: Multiple Myelomamentioning

confidence: 99%

“…Ruxolitinib has been approved for the treatment of myelofibrosis [140] and polycythemia vera [141]. Ruxolitinib has shown promising antitumor activity in preclinical studies of ABC DLBCL [35], ATLL [142], and MM [117]. Ruxolitinib is currently under a phase 2 clinical study in DLBCL and T-cell non-Hodgkin lymphoma (NCT01431209), a phase 1 trial in MM (NCT03110822), and a clinical investigation in adult T-cell leukemia (ATL) (NCT01712659).…”

Section: Upstream Inhibition Of Stat3mentioning

confidence: 99%

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STAT3 Activation and Oncogenesis in Lymphoma

Zhu

Wang²,

2019

Cancers

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Signal transducer and activator of transcription 3 (STAT3) is an important and the most studied transcription factor in the Janus kinase (JAK)/STAT signaling pathway. STAT3 mediates the expression of various genes that play a critical role in many cellular and biological processes, such as cell proliferation, survival, differentiation, migration, angiogenesis, and inflammation. STAT3 and associated JAKs are activated and tightly regulated by a variety of cytokines and growth factors and their receptors in normal immune responses. However, abnormal expression of STAT3 leads to its constitutive activation, which promotes malignant transformation and tumor progression through oncogenic gene expression in numerous human cancers. Human lymphoma is a heterogeneous malignancy of T and B lymphocytes. Constitutive signaling by STAT3 is an oncogenic driver in several types of B-cell lymphoma and most of T-cell lymphomas. Aberrant STAT3 activation can also induce inappropriate expression of genes involved in tumor immune evasion such as PD-L1. In this review, we focus on the oncogenic role of STAT3 in human lymphoma and highlight potential therapeutic intervention by targeting JAK/STAT3 signaling.

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Section: Multiple Myelomamentioning

confidence: 99%

Section: Upstream Inhibition Of Stat3mentioning

confidence: 99%

STAT3 Activation and Oncogenesis in Lymphoma

Zhu

Wang²,

2019

Cancers

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“…Our present report bears an intriguing precision‐oncology theme, noting that the initiation of ruxolitinib was followed by myeloma haematological response. The role of ruxolitinib in the treatment of myeloma has been investigated previously (Chen et al , ; de Oliveira et al , ; Ogiya et al , ; Chen et al , ; Berenson et al , ). Bortezomib and ruxolitinib treatment induced apoptosis and decreased expression of B cell leukaemia/lymphoma 2 (BCL‐2) and B cell lymphoma extra‐large (BCL‐XL) in myeloma cells (de Oliveira et al , ).…”

Section: Discussionmentioning

confidence: 99%

“…The role of ruxolitinib in the treatment of myeloma has been investigated previously (Chen et al , ; de Oliveira et al , ; Ogiya et al , ; Chen et al , ; Berenson et al , ). Bortezomib and ruxolitinib treatment induced apoptosis and decreased expression of B cell leukaemia/lymphoma 2 (BCL‐2) and B cell lymphoma extra‐large (BCL‐XL) in myeloma cells (de Oliveira et al , ). Other studies have suggested a role for combination treatment with ruxolitinib to enhance the efficacy of CD38‐targetting immunotherapies (Ogiya et al , ).…”

Section: Discussionmentioning

confidence: 99%

Anti‐myeloma potential of ruxolitinib in co‐existing JAK2V617F‐positive smouldering myeloma and polycythaemia vera

et al. 2020

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“…For instance, the JAK2 inhibitor TG101209 induced dose-and time-dependent cytotoxicity in a variety of MM cell lines by inhibiting cell cycle progression and inducing apoptosis in MM cell lines and patients' derived plasma cells [48] . Ruxolitinib, a tyrosine kinase inhibitor, TM-233, a novel analogue of 1' -acetoxychavicol acetate, and cantharidin induced cell death in in vitro models of MM [49][50][51] . The gold compound auranofin induced apoptosis of human MM cells through both down-regulation of STAT3 and inhibition of NF-κB activity [52] .…”

Section: Jak/stat Signaling Pathwaymentioning

confidence: 99%

Drug targets and resistance mechanisms in multiple myeloma

Naß¹,

Efferth²

2018

CDR

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Multiple myeloma (MM), a malignancy of plasma cells, is the second most prevalent blood cancer (10%). A PubMed search has been conducted for English research papers and reviews published until January 2018. Numerous drugs are used in treatment of MM. These include the antineoplastic alkylating agents cyclophosphamide, busulfan and melphalan, immunomodulators such as lenalidomide and thalidomide, corticosteroids including dexamethasone, microtubule-targeting agents, such as paclitaxel and vinca alkaloids, as well as the proteasome inhibitors bortezomib and carfilzomib. Despite the considerable number of treatment options, MM is still difficult to treat, which is mirrored by the poor 10-year survival rate of 3%. Resistance to chemotherapy is often the cause for therapy failure. These resistances can be due to the overexpression of efflux pumps, genetic and epigenetic aberrations and the microenvironment of MM. With the gain of knowledge regarding genetic and molecular changes, many molecular targeted therapies including cell signaling targeted therapies are being developed against relapsed/refractory MM. Additionally, epigenetic aberrations such as DNA methylation and histone modifications steered MM management in new directions. Amongst these novel targeted therapies, inhibitors of histone deacetylase, Aurora kinase, inhibitors of the PI3K/AKT/mTOR pathway and cyclin dependent kinases are promising.

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Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for JAK/STAT pathway inhibition in myeloma patients

Cited by 33 publications

References 27 publications

STAT3 Activation and Oncogenesis in Lymphoma

STAT3 Activation and Oncogenesis in Lymphoma

Anti‐myeloma potential of ruxolitinib in co‐existing JAK2V617F‐positive smouldering myeloma and polycythaemia vera

Drug targets and resistance mechanisms in multiple myeloma

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