Targeting STAT3 by a small molecule suppresses pancreatic cancer progression

Huang, Chengdu; Bian, Aiwu; Yang, Lian-Fang; Yin, Xuan; Wang, Jie; Ti, Chaowen; Miao, Ying; Peng, Shihong; Xu, Shi‐Hai; Liu, Mingyao; Qiu, Wen‐Wei; Yi, Zhengfang

doi:10.1038/s41388-020-01626-z

Cited by 46 publications

(45 citation statements)

References 41 publications

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“…N4 suppresses tumor growth and metastasis in animal models of pancreatic cancer. After 20 days of treatment with 20 μM/kg N4 in pancreatic cancer‐bearing mice, the tumor weights of the mice were significantly lower than those of the control group ( p < 0.0001, n = 6) 295 …”

Section: Stat3 As a Therapeutic Target In Cancer Treatmentmentioning

confidence: 88%

“…After 20 days of treatment with 20 μM/kg N4 in pancreatic cancer-bearing mice, the tumor weights of the mice were significantly lower than those of the control group (p < 0.0001, n = 6). 295 Wang et al reported that HJC0152, designed as an O-alkylaminotethered derivative of niclosamide, can inhibit p-STAT3 (Tyr705) and decrease the invasion and migration ability of HNSCC cells. 296 LY5 was designed as a small-molecule inhibitor that blocks the phosphotyrosine-binding site of the SH2 domain at nanomolar concentrations.…”

Section: Blocking Dimerizationmentioning

confidence: 99%

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STAT3 pathway in cancers: Past, present, and future

Wang

Man

Huo

et al. 2022

MedComm

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Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, discovered in the cytoplasm of almost all types of mammalian cells, plays a significant role in biological functions. The duration of STAT3 activation in normal tissues is a transient event and is strictly regulated. However, in cancer tissues, STAT3 is activated in an aberrant manner and is induced by certain cytokines. The continuous activation of STAT3 regulates the expression of downstream proteins associated with the formation, progression, and metastasis of cancers. Thus, elucidating the mechanisms of STAT3 regulation and designing inhibitors targeting the STAT3 pathway are considered promising strategies for cancer treatment. This review aims to introduce the history, research advances, and prospects concerning the STAT3 pathway in cancer. We review the mechanisms of STAT3 pathway regulation and the consequent cancer hallmarks associated with tumor biology that are induced by the STAT3 pathway. Moreover, we summarize the emerging development of inhibitors that target the STAT3 pathway and novel drug delivery systems for delivering these inhibitors. The barriers against targeting the STAT3 pathway, the focus of future research on promising targets in the STAT3 pathway, and our perspective on the overall utility of STAT3 pathway inhibitors in cancer treatment are also discussed.

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Section: Stat3 As a Therapeutic Target In Cancer Treatmentmentioning

confidence: 88%

Section: Blocking Dimerizationmentioning

confidence: 99%

STAT3 pathway in cancers: Past, present, and future

Wang

Man

Huo

et al. 2022

MedComm

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“…Genes regulated by YAP are involved in proliferation and invasion in PDAC. 42 43 We sought to evaluate the role of YAP in mediating the phenotype observed on modulation of the EVNet, which occurs mainly through CSC agrin + EVs signalling. To this end, we performed an MTT assay using NSCC treated with CSC EVs in the presence or absence of verteporfin, a YAP inhibitor.…”

Section: Agrin-positive Csc Evs Promote Yap Activationmentioning

confidence: 99%

Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression

Ruivo

Bastos

Adem

et al. 2022

Gut

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ObjectiveIntratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour.DesignWe have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC). To determine the biological significance of the most frequent communication route, we used pancreatic ductal adenocarcinoma (PDAC) orthotopic models, patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs).ResultsWe demonstrate that PDAC tumours establish an organised communication network between subpopulations of cancer cells using EVs called the EVNet). The EVNet is plastic and reshapes in response to its environment. Communication within the EVNet occurs preferentially from CSC to NSCC. Inhibition of this communication route by impairing Rab27a function in orthotopic xenographs, GEMMs and PDXs is sufficient to hamper tumour growth and phenocopies the inhibition of communication in the whole tumour. Mechanistically, we provide evidence that CSC EVs use agrin protein to promote Yes1 associated transcriptional regulator (YAP) activation via LDL receptor related protein 4 (LRP-4). Ex vivo treatment of PDXs with antiagrin significantly impairs proliferation and decreases the levels of activated YAP.Patients with high levels of agrin and low inactive YAP show worse disease-free survival. In addition, patients with a higher number of circulating agrin+ EVs show a significant increased risk of disease progression.ConclusionPDAC tumours establish a cooperation network mediated by EVs that is led by CSC and agrin, which allows tumours to adapt and thrive. Targeting agrin could make targeted therapy possible for patients with PDAC and has a significant impact on CSC that feeds the tumour and is at the centre of therapy resistance.

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“…Correlative studies with paired biopsies in PDAC patients show increased proliferating CD8+ T cells, while Tregs, macrophages, and stromal density decreased with treatment [159]. FAK inhibition's limited clinical efficacy may be in part related to a resistance mechanism via STAT3 upregulation triggered by FAK-induced stromal depletion, arguing for a combinational approach with direct/ indirect STAT3 inhibitors [160,161].…”

Section: Il-1β Antagonismmentioning

confidence: 99%

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

Heumann

Azad

2021

Cancer Metastasis Rev

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To date, the use of immune checkpoint inhibitors has proven largely ineffective in patients with advanced pancreatic ductal adenocarcinoma. A combination of low tumor antigenicity, deficits in immune activation along with an exclusive and suppressive tumor microenvironment result in resistance to host defensives. However, a deepening understanding of these immune escape and suppressive mechanisms has led to the discovery of novel molecular targets and treatment strategies that may hold the key to a long-awaited therapeutic breakthrough. In this review, we describe the tumor-intrinsic and microenvironmental barriers to modern immunotherapy, examine novel immune-based and targeted modalities, summarize relevant pre-clinical findings and human experience, and, finally, discuss novel synergistic approaches to overcome immune-resistance in pancreatic cancer. Beyond checkpoint inhibition, immune agonists and anti-tumor vaccines represent promising strategies to stimulate host response via activation and expansion of anti-tumor immune effectors. Off-the-shelf natural killer cell therapies may offer an effective method for bypassing downregulated tumor antigen presentation. In parallel with this, sophisticated targeting of crosstalk between tumor and tumor-associated immune cells may lead to enhanced immune infiltration and survival of antitumor lymphocytes. A future multimodal treatment strategy involving immune priming/activation, tumor microenvironment reprogramming, and immune checkpoint blockade may help transform pancreatic cancer into an immunogenic tumor.

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Targeting STAT3 by a small molecule suppresses pancreatic cancer progression

Cited by 46 publications

References 41 publications

STAT3 pathway in cancers: Past, present, and future

STAT3 pathway in cancers: Past, present, and future

Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

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