Targeting STAT3 in Cancer Immunotherapy

Nemati

2021

Microbial Pathogenesis

Hyper-inflammatory responses, lymphopenia, unbalanced immune responses, cytokine storm, large viral replication and massive cell death play fundamental roles in the pathogenesis of COVID-19. Extreme production of many kinds of pro-inflammatory cytokines and chemokines occur in severe COVID-19 that called cytokine storm. Signal transducer and activator of transcription-3 (STAT-3) present in the cytoplasm in an inactive form and can be stimulated by a vast range of cytokines, chemokines and growth factors. Thus, STAT-3 can participate in the induction of inflammatory responses during coronavirus infections. STAT-3 can also suppress anti-virus interferon response and induce unbalanced anti-virus adaptive immune response, through influencing Th17-, Th1-, Treg-, and B cell-mediated functions. Furthermore, STAT-3 can contribute to the M2 macrophage polarization, lung fibrosis and thrombosis. Moreover, STAT-3 may be directly targeted by some virus-derived protein and operate as a pro-viral or anti-viral element in a virus-specific process. Here, the possible contribution of STAT-3 to the pathogenesis of COVID-19 was explained, while providing potential approaches to target this transcription factor in an attempt for COVID-19 treatment.

Section: Targeting Of Stat-3mentioning

confidence: 99%

“…Post-translational alterations such as methylation, acetylation and sumoylation can control STAT-3 activity via changing the STAT-3 phosphorylation. STAT-3 activity also can be directly and indirectly modulated by noncoding RNAs such as miRNAs and long non-coding RNAs [ 108 ].…”

Section: Targeting Of Stat-3mentioning

confidence: 99%

Contribution of STAT3 to the pathogenesis of COVID-19

Nemati

2021

Microbial Pathogenesis

“…The therapeutic antisense oligonucleotide danvatirsen (formerly IONIS-STAT3-2.5Rx; AZD9150), inhibits the production of STAT3 by binding to STAT3 mRNA [96]. Preclinical data have suggested that STAT3 inhibition combined with immunotherapy may enhance therapeutic effectiveness and reduce immunotherapy resistance [97]. This was clinically validated in a phase Ib/II clinical trial treating 38 patients with PD-L1-naïve advanced solid tumours and recurrent/metastatic head and neck cancer with danvatirsen combined with durvalumab (an anti-PD-L1 antibody) as second-line treatment (NCT02499328) [98].…”

Section: Stat3 Inhibitionmentioning

confidence: 99%

The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies

García-Sampedro

Gaggia

Ney

et al. 2021

JCM

Pancreatic cancer is a devastating disease with very poor prognosis. Currently, surgery followed by adjuvant chemotherapy represents the only curative option which, unfortunately, is only available for a small group of patients. The majority of pancreatic cancer cases are diagnosed at advanced or metastatic stage when surgical resection is not possible and treatment options are limited. Thus, novel and more effective therapeutic strategies are urgently needed. Molecular profiling together with targeted therapies against key hallmarks of pancreatic cancer appear as a promising approach that could overcome the limitations of conventional chemo- and radio-therapy. In this review, we focus on the latest personalised and multimodal targeted therapies currently undergoing phase II or III clinical trials. We discuss the most promising findings of agents targeting surface receptors, angiogenesis, DNA damage and cell cycle arrest, key signalling pathways, immunotherapies, and the tumour microenvironment.

“…The third potential target in the IL-6 signaling pathway is STAT3, with several compounds inhibiting the function or expression of STATs in clinical trials for various solid tumors [ 69 ]. BBI608, an oral cancer stemness inhibitor that blocks STAT3-mediated transcription of cancer stemness genes in the β-catenin pathway, has reached Phase II and III to treat metastatic colorectal cancer ( Table 1 ).…”

Section: Clinical Trials Targeting Pro-inflammatory Cytokines In Mmentioning

confidence: 99%

Pro-Inflammatory Cytokines in the Formation of the Pre-Metastatic Niche

Wen

Lin

2020

Cancers

In the presence of a primary tumor, the pre-metastatic niche is established in secondary organs as a favorable microenvironment for subsequent tumor metastases. This process is orchestrated by bone marrow-derived cells, primary tumor-derived factors, and extracellular matrix. In this review, we summarize the role of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β, CC-chemokine ligand 2 (CCL2), granulocyte-colony stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), stromal cell-derived factor (SDF)-1, macrophage migration inhibitory factor (MIF), and Chemokine (C–X–C motif) ligand 1 (CXCL1) in the formation of the pre-metastatic niche according to the most recent studies. Pro-inflammatory cytokines released from tumor cells or stromal cells act in both autocrine and paracrine manners to induce phenotype changes in tumor cells, recruit bone marrow-derived cells, and form an inflammatory milieu, all of which prime a secondary organ’s microenvironment for metastatic cell colonization. Considering the active involvement of pro-inflammatory cytokines in niche formation, clinical strategies targeting them offer ways to inhibit the establishment of the pre-metastatic niche and therefore attenuate metastatic progression. We review clinical trials targeting different inflammatory cytokines in patients with metastatic cancers. Due to the pleiotropy and redundancy of pro-inflammatory cytokines, combined therapies should be designed in the future.