JAK2 inhibition for the treatment of hematologic and solid malignancies

Harry, Brian L.; Eckhardt, S. Gail; Jimeno, Antonio

doi:10.1517/13543784.2012.677432

Cited by 27 publications

(22 citation statements)

References 139 publications

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“…In clear contrast, several Janus kinase (JAK) inhibitors that block upstream signaling are in clinical development. Selected orally available and adenosine triphosphate (ATP)-competitive small-molecule JAK kinase inhibitors (ruxolitinib (INC424), SAR302503 (TG101348), pacritinib (SB1518), CYT387, AZD1480, tasocitinib, INCB028050, CEP-701, XL019) have already been tested in clinical trials for myelofibrosis and rheumatoid arthritis, for pancreatic and breast cancer, and for hematologic malignancies [ 11 , 148 , 149 , 150 ]. Small-molecule inhibitors that interfere with STAT3 upstream signaling have also been developed for Src kinase.…”

Section: Stat3 Inhibitors In Clinical Translationmentioning

confidence: 99%

“…Obviously, as JAK/STAT signaling controls a variety of cellular processes and affects the microenvironment, as well as the immune system, therapeutic targeting may have a wide range of systemic ramifications [ 11 , 145 , 150 , 157 ]. For instance, chronic exposure to JAK inhibitors can result in hematologic toxicities, such as anemia and thrombocytopenia, and gastrointestinal disturbances [ 148 , 149 ]. Pertinent to the latter, very recent evidence indicates that STAT3 inhibition may impair the host protection from intestinal bacterial infection and increase the risk for pathogen-mediated diarrhea [ 158 ].…”

Section: Stat3 Inhibitors In Clinical Translationmentioning

confidence: 99%

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STAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy

Spitzner¹,

Ebner

Wolff³

et al. 2014

Cancers

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Chemoradiotherapy (CRT) represents a standard treatment for many human cancers, frequently combined with radical surgical resection. However, a considerable percentage of primary cancers are at least partially resistant to CRT, which represents a substantial clinical problem, because it exposes cancer patients to the potential side effects of both irradiation and chemotherapy. It is therefore exceedingly important to determine the molecular characteristics underlying CRT-resistance and to identify novel molecular targets that can be manipulated to re-sensitize resistant tumors to CRT. In this review, we highlight much of the recent evidence suggesting that the signal transducer and activator of transcription 3 (STAT3) plays a prominent role in mediating CRT-resistance, and we outline why inhibition of STAT3 holds great promise for future multimodal treatment concepts in oncology.

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Section: Stat3 Inhibitors In Clinical Translationmentioning

confidence: 99%

Section: Stat3 Inhibitors In Clinical Translationmentioning

confidence: 99%

STAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy

Spitzner¹,

Ebner

Wolff³

et al. 2014

Cancers

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“…Briefly, the kinase domain is located on the C-terminus of the molecule and is preceded by a pseudokinase domain, which is structurally similar, and, in JAK2, has been shown to phosphorylate two negative regulatory sites and therefore serving an important regulatory role (6). The relative importance of the pseudokinase domain has become apparent when mutations in this domain in JAK2 have been shown to be the cause of various hematologic disorders (7). Next to the pseudokinase domain is a Src Homology 2 (SH2) domain, which could be indicative of a capacity to recognize and bind phosphorylated tyrosine residues (although this has not yet been proven).…”

Section: Cytokine Receptor Signaling: the Jak-stat Cascadementioning

confidence: 99%

The Arrival of JAK Inhibitors: Advancing the Treatment of Immune and Hematologic Disorders

Furumoto

Gadina

2013

BioDrugs

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Altered production of cytokines can result in pathologies ranging from autoimmune diseases to malignancies. The Janus Kinases family is a small group of receptor-associated signaling molecules that is essential to the signal cascade originating from type I and type II cytokine receptors. Inhibition of tyrosine kinases enzymatic activity using small molecules has recently become a powerful tool for treatment of several malignancies. Twenty years after the discovery of these enzymes, two inhibitors for this class of kinases have been approved for clinical use and others are currently in the final stage of development. Here we review the principles of cytokines signaling, we summarize our current knowledge of the approved inhibitors, and briefly introduce some of the inhibitors that are currently under development.

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“…A growing body of evidence demonstrates that the activation of the Jak2 signaling pathway is required for the growth of solid tumor cells. Jak2 was reported to be overexpressed in breast cancer [3,4], which promotes malignant cell survival and growth by modulating cell apoptosis partly through the up-regulation of Bcl-2 family members, such as mcl-1, Bcl-xl, and Bcl-2 [5,6]. …”

Section: Introductionmentioning

confidence: 99%

miR-101 Promotes Breast Cancer Cell Apoptosis by Targeting Janus Kinase 2

Wang

Guo

et al. 2014

Cell Physiol Biochem

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Aims: microRNA-101 (miR-101) is down-regulated in several cancers. In this study, we explored the effects of dysregulated miR-101 on breast cancer cells and the underlying mechanisms. Methods: miR-101 level was quantified by real-time RT-PCR. Cell viability was analyzed by MTT assay. Apoptosis was detected by flow cytometry and TUNEL assay. Moreover, the level of protein expression was determined by Western blot. Results: miR-101 level was markedly reduced in both the human breast cancer samples and cultured breast cancer cell lines (MCF-7, MDA-MB-231). Overexpression of miR-101 inhibited the proliferation and promoted the apoptosis in cultured MCF-7 and MDA-MB-231 cells, which were reversed by co-transfection of AMO-101, the inhibitor of miR-101. We validated Janus kinase 2 (Jak2) as a direct target of miR-101. Knockdown of Jak2 induced apoptosis in cultured breast cancer cells. Moreover, the level of miR-101 is negatively correlated with Jak2 in breast cancer tissues and cell lines. Conclusions: miR-101 suppressed proliferation and promoted apoptosis in breast cancer cells by targeting Jak2. These findings indicate that manipulation of miR-101 expression may represent a novel therapeutic strategy in the treatment of breast cancer.

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JAK2 inhibition for the treatment of hematologic and solid malignancies

Cited by 27 publications

References 139 publications

STAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy

STAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy

The Arrival of JAK Inhibitors: Advancing the Treatment of Immune and Hematologic Disorders

miR-101 Promotes Breast Cancer Cell Apoptosis by Targeting Janus Kinase 2

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