Novel activators and small-molecule inhibitors of STAT3 in cancer

Yang, Lehe; Lin, Shichong; Xu, Linhao; Lin, Jiayuh; Zhao, Chengguang; Huang, Xiaoying

doi:10.1016/j.cytogfr.2019.10.005

Cited by 107 publications

(85 citation statements)

References 118 publications

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“…It is also being trialed in lung, advanced pancreatic, and mismatch repair-deficient colorectal cancers in combination with the anti-PD-L1 checkpoint inhibitor, Durvalumab (NCT02983578); in advanced solid tumors in combination with Durvalumab and chemotherapy (NCT03421353); and, in treatment-refractory non-Hodgkin's lymphoma in combination with acalabrutinib (NCT03527147), with no results reported at this time. Napabucasin, which inhibits STAT3-mediated transcription of target genes that regulate stemness, such as Nanog, is in phase III trial for patients with metastatic colorectal cancer in combination with the trichemotherapeutic, FOLFIRI (NCT03522649), and metastatic pancreatic adenocarcinoma in combination with nab-paclitaxel and gemcitabine (NCT02993731), along with several other phase I studies in other cancers, with positive patient outcomes being associated with safety and tolerance already reported in several solid tumor types [214][215][216]. Napabucasin has been demonstrated to sensitize tumor cells to checkpoint inhibition and it has been linked to high tumor infiltration of CD8 + T cells in mice bearing 4T1 mammary tumors [217], with similar results being reported in mesothelioma [218].…”

Section: Therapeutic Modulation Of Statsmentioning

confidence: 99%

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

435

326

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Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.2 of 26 role in pathogenesis [3]. Yet, despite the seemingly linear order of events, the impact of mutations, selective dimerization, negative pathway regulation, and post-translational modifications of pathway members has branded the JAK-STAT axis a complex signaling cascade, of which many regulatory processes are still poorly understood.STATs have emerged as somewhat of a double-edged sword, being widely explored in the context of cancer. While several members of the STAT family, which encompasses STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 as a whole, have been linked to tumor initiation and progression (STAT3 and STAT5), others are integral in antitumor defense and the maintenance of an effective and long-term immune response (STAT1 and STAT2) through evolutionarily conserved programs [1]. With increasing emphasis on immune-based agents as important therapeutics in the fight against solid tumor growth and spread, understanding the function of STAT specificity, redundancy, and connectedness in cancer is a critical component of achieving immunotherapeutic augmentation and success.Here, we investigate the good and the bad of STAT signaling in the context of immune regulation and cancer, and discuss how STATs can be targeted to bolster antitumor immune defense. JAK-STAT Signaling and InterferonsThe presence of stimulatory or inhibitory signals governs the innate and adaptive immune activity that controls both effective immune surveillance and facilitates escape. Such signals determine the fate of plastic immune cells, such as T lymphocytes, and regulate their recruitment, survival, status, and eventual death ...

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Section: Therapeutic Modulation Of Statsmentioning

confidence: 99%

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

435

326

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“…To date, no direct STAT3/5b inhibitors of clinical grade are available. However, early-phase clinical trials with drugs targeting STAT3 are ongoing in solid and hematologic malignancies other than LGLL, namely AZD9150, a STAT3 antisense oligonucleotide, and Napabucasin, an inhibitor of gene expression driven by STAT3 (56). In LGLL some compounds against the upstream signaling to STAT have been tested, with preliminary promising results.…”

Section: The Clinical Impact Of Stat3 and Stat5b Mutationsmentioning

confidence: 99%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

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Large granular lymphocyte leukemia (LGLL) is a chronic proliferation of clonal cytotoxic lymphocytes, usually presenting with cytopenias and yet lacking a specific therapy. The disease is heterogeneous, including different subsets of patients distinguished by LGL immunophenotype (CD8+ Tαβ, CD4+ Tαβ, Tγδ, NK) and the clinical course of the disease (indolent/symptomatic/aggressive). Even if the etiology of LGLL remains elusive, evidence is accumulating on the genetic landscape driving and/or sustaining chronic LGL proliferations. The most common gain-of-function mutations identified in LGLL patients are on STAT3 and STAT5b genes, which have been recently recognized as clonal markers and were included in the 2017 WHO classification of the disease. A significant correlation between STAT3 mutations and symptomatic disease has been highlighted. At variance, STAT5b mutations could have a different clinical impact based on the immunophenotype of the mutated clone. In fact, they are regarded as the signature of an aggressive clinical course with a poor prognosis in CD8+ T-LGLL and aggressive NK cell leukemia, while they are devoid of negative prognostic significance in CD4+ T-LGLL and Tγδ LGLL. Knowing the specific distribution of STAT mutations helps identify the discrete mechanisms sustaining LGL proliferations in the corresponding disease subsets. Some patients equipped with wild type STAT genes are characterized by less frequent mutations in different genes, suggesting that other pathogenetic mechanisms are likely to be involved. In this review, we discuss how the LGLL mutational pattern allows a more precise and detailed tumor stratification, suggesting new parameters for better management of the disease and hopefully paving the way for a targeted clinical approach.

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“…AZD9150 is currently under clinical trials for aggressive non-Hodgkin lymphoma (NCT03527147) and nonsmall cell lung cancer (NCT03334617). Napabucasin (or BBI608), which can inhibit gene expression driven by STAT3 and cancer stemness [138], is being clinically evaluated in solid cancers [139].…”

Section: Direct Stat3 Inhibitionmentioning

confidence: 99%

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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Novel activators and small-molecule inhibitors of STAT3 in cancer

Cited by 107 publications

References 118 publications

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

STAT3 Activation and Oncogenesis in Lymphoma

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