Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma

Baran‐Marszak, Fanny; Boukhiar, Mohand; Harel, Stéphanie; Laguillier, Christelle; Roger, Claudine; Gressin, Rémy; Martin, Antoine; Fagard, Rémi; Varin‐Blank, Nadine; Ajchenbaum‐Cymbalista, Florence; Ledoux, Dominique

doi:10.3324/haematol.2009.019745

Cited by 65 publications

(63 citation statements)

References 34 publications

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“…Inactivating mutations of SOCS1, an inhibitor of the JAK/STAT pathway, have been described in some MCLs (47). Interestingly, STAT3 activation seems to be more common in MCLs with hypermutated (compared with unmutated) IGHV, suggesting that these two subtypes of MCL may use different cell survival mechanisms (43).…”

Section: Signaling Pathways Deregulated In MCLmentioning

confidence: 99%

Section: Signaling Pathways Deregulated In MCLmentioning

confidence: 99%

“…Phosphorylated STAT3 has been observed in primary MCL (43,44). This activation may occur through a cytokine-dependent autocrine IL-6 and/or IL-10 secretion loop and/or induced upon BCR engagement (43). The IL-10 receptor is overexpressed in some MCLs (45), and IL-10 has been shown to sustain cell proliferation in MCL primary cells (46).…”

Section: Signaling Pathways Deregulated In MCLmentioning

confidence: 99%

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Molecular pathogenesis of mantle cell lymphoma

Jares

Colomer²,

Campo³

2012

J. Clin. Invest.

328

302

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Mantle cell lymphoma is a B cell malignancy in which constitutive dysregulation of cyclin D1 and the cell cycle, disruption of DNA damage response pathways, and activation of cell survival mechanisms contribute to oncogenesis. A small number of tumors lack cyclin D1 overexpression, suggesting that its dysregulation is always not required for tumor initiation. Some cases have hypermutated IGHV and stable karyotypes, a predominant nonnodal disease, and an indolent clinical evolution, which suggests that they may correspond to distinct subtypes of the disease. In this review, we discuss the molecular pathways that contribute to pathogenesis, and how improved understanding of these molecular mechanisms offers new perspectives for the treatment of patients. IntroductionMantle cell lymphoma (MCL) is a B cell malignancy with a broad spectrum of clinical, pathological, and biological features. The identification of the translocation event t(11;14)(q13;q32) and the resulting cyclin D1 overexpression were of paramount importance in recognizing the clinical and biological diversity of this tumor. In addition to this constitutive dysregulation of the cell cycle, other mechanisms such as DNA damage response alterations and activation of cell survival pathways are integrated to drive MCL pathogenesis (1, 2). New observations are expanding our views on the ontogeny and pathogenesis of this lymphoma. Furthermore, these new insights into MCL oncogenesis are promoting the development of new therapeutic strategies, intended to target the molecular mechanism of the disease, and opening up new clinical perspectives for optimal diagnosis and management of the patients.

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Section: Signaling Pathways Deregulated In MCLmentioning

confidence: 99%

Section: Signaling Pathways Deregulated In MCLmentioning

confidence: 99%

Section: Signaling Pathways Deregulated In MCLmentioning

confidence: 99%

See 1 more Smart Citation

Molecular pathogenesis of mantle cell lymphoma

Jares

Colomer²,

Campo³

2012

J. Clin. Invest.

328

302

View full text Add to dashboard Cite

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“…These include diseases of autoreactivity, such as that observed in lupus, multiple sclerosis, and rheumatoid arthritis, in which B cells inappropriately break self-tolerance to produce antibodies contributing to autoimmune disease Cambridge, 2005, 2006;Teng et al, 2007). BCR signaling also contributes to several B cell malignancies, such as chronic lymphocytic leukemia (CLL) (Chen et al, 2005;Hoellenriegel et al, 2011;Stevenson et al, 2011), mantle cell lymphoma, and subsets of diffuse large B cell leukemia (Chen et al, 2008;Lenz et al, 2008;Baran-Marszak et al, 2010;Davis et al, 2010;Suljagic et al, 2010;Pighi et al, dx.doi.org/10.1124/jpet.113.203489. s This article has supplemental material available at jpet.aspetjournals.org.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans

Evans¹,

Tester²,

Aslanian³

et al. 2013

J Pharmacol Exp Ther

205

219

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Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.

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“…Furthermore, we can't exclude the potential impact of miR-124 on the B cells in mediating a therapeutic effect. Notably, this approach may have therapeutic utility in the setting of lymphoma 23 because LUNAR-301 can potentially target STAT3 within B cells.…”

Section: Neurooncologymentioning

confidence: 99%

Immune modulatory nanoparticle therapeutics for intracerebral glioma

Yaghi¹,

Wei²,

Hashimoto³

et al. 2016

NEUONC

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372Most preclinical therapeutic studies of microRNAs (miRs) and small interfering (si)RNAs have provided "proof of principle" that upon ex vivo transfection of cancer cells, a therapeutic effect can be obtained. [1][2][3] We previously demonstrated that the need to transfect could potentially be overcome by using miR to directly modulate the immune system and initiate antitumor cytotoxicity. 4 Malignant cells express various antigens recognized by the immune system, but antitumor cytotoxicity is restrained by signal transducer and activator of transcription 3 (STAT3) signaling. [5][6][7][8] We have identified miR-124 as a key regulator of the STAT3 pathway and shown that systemically administered miR-124 has marked therapeutic effects in preclinical malignancy models, including in established, heterogeneous, highgrade, genetically engineered murine models during late stages of gliomagenesis. 4 These therapeutic effects encompass marked enhancement of antitumor immunity, including interferon (IFN)-γ responses, and reversal of tumor-mediated immunosuppression. 4 AbstractBackground. Previously we showed therapeutic efficacy of unprotected miR-124 in preclinical murine models of glioblastoma, including in heterogeneous genetically engineered murine models by exploiting the immune system and thereby negating the need for direct tumor delivery. Although these data were promising, to implement clinical trials, we required a scalable formulation that afforded protection against circulatory RNases. Methods. We devised lipid nanoparticles that encapsulate and protect the miRs from degradation and provide enhanced delivery into the immune cell compartment and tested in vivo antitumor effects. Results. Treatment with nanoparticle-encapsulated miR-124, LUNAR-301, demonstrated a median survival exceeding 70 days, with an associated reversal of tumor-mediated immunosuppression and induction of immune memory. In both canine and murine models, the safety profile of LUNAR-301 was favorable. Conclusions. For the first time, we show that nanoparticles can direct a therapeutic response by targeting intracellular immune pathways. Although shown in the context of gliomas, this therapeutic approach would be applicable to other malignancies.

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Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma

Cited by 65 publications

References 34 publications

Molecular pathogenesis of mantle cell lymphoma

Molecular pathogenesis of mantle cell lymphoma

Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans

Immune modulatory nanoparticle therapeutics for intracerebral glioma

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