Special Issue "Targeting STAT3 and STAT5 in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 30 September 2019

Special Issue Editors

Guest Editor
Prof. Dr. Richard Moriggl

Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria Medical University Vienna, Vienna, Austria
Website | E-Mail
Interests: cytokine signaling; JAK-STAT pathway; basic and translational cancer research; targeting transcription factors; core cancer pathways; chromatin remodeling
Guest Editor
Prof. Dr. Patrick Gunning

Department of Chemical & Physical Sciences, University Toronto Mississauga, Canada
Website | E-Mail
Interests: molecular therapeutics; drug discovery; medicinal chemistry; protein–protein interactions; JAK–STAT pathway
Guest Editor
Prof. Dr. György Miklós Keserü

Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary
Website | E-Mail
Interests: drug design; fragment-based drug discovery; medicinal chemistry; drug discovery

Special Issue Information

Dear Colleagues,

Cancer is driven by hyperactivation of the JAK–STAT core cancer pathways associated with inappropriate functions of normal signaling pathways involving cytokine, growth factor and hormone action. The successful implementation of clinically approved JAK kinase inhibitors (baracitinib, ruxolitinib and tofacitinib) is proof that JAK–STAT targeting is beneficial. Consequently, targeting oncogenic transcription factors of the STAT family, namely STAT3, STAT5A and STAT5B as major funnels for gene regulatory processes including chromatin remodeling facilitated by them has therapeutic power. STAT3/5 proteins are attractive targets for drug discovery since they steer proliferation, survival and metabolism. Targeting protein-protein interactions, however, is challenging since the interacting surfaces are typically large and flat, having non-contiguous binding hot spots and lack of deep tractible pockets. Furthermore, targeting transcription factors is considered “undruggable”. Emerging drug design strategies and medicinal chemistry approaches, including methods to impair function, to destabilize or degrade transcription factors or to interfere with interaction partners and cofactors, initiated new concepts. Here, we summarize targeting approaches on STAT3/5, where the field moves into clinical application. We cover the design paradigms and medicinal chemistry approaches to illuminate limitations in specificity, potency, and in vivo bioavailability, necessitating approaches.

Focus of this special issue:

STAT3/5 activation is at the convergence point of many signaling pathways, activated by a plethora of upstream kinases and STAT3- and STAT5-targeting approaches in cancer is up for article invitation for this Special Issue.

Prof. Dr. Richard Moriggl
Prof. Dr. Patrick Gunning
Prof. Dr. György Miklós Keserü
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • STAT3
  • STAT5A
  • STAT5B
  • JAK kinases
  • oncogene induction
  • metabolism
  • chromatin remodeling
  • blockade of dimer formation

Published Papers (2 papers)

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Research

Open AccessArticle Therapeutic Targeting of Stat3 Using Lipopolyplex Nanoparticle-Formulated siRNA in a Syngeneic Orthotopic Mouse Glioma Model
Cancers 2019, 11(3), 333; https://doi.org/10.3390/cancers11030333
Received: 21 December 2018 / Revised: 25 February 2019 / Accepted: 4 March 2019 / Published: 8 March 2019
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Abstract
Glioblastoma (GBM), WHO grade IV, is the most aggressive primary brain tumor in adults. The median survival time using standard therapy is only 12–15 months with a 5-year survival rate of around 5%. Thus, new and effective treatment modalities are of significant importance. [...] Read more.
Glioblastoma (GBM), WHO grade IV, is the most aggressive primary brain tumor in adults. The median survival time using standard therapy is only 12–15 months with a 5-year survival rate of around 5%. Thus, new and effective treatment modalities are of significant importance. Signal transducer and activator of transcription 3 (Stat3) is a key signaling protein driving major hallmarks of cancer and represents a promising target for the development of targeted glioblastoma therapies. Here we present data showing that the therapeutic application of siRNAs, formulated in nanoscale lipopolyplexes (LPP) based on polyethylenimine (PEI) and the phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), represents a promising new approach to target Stat3 in glioma. We demonstrate that the LPP-mediated delivery of siRNA mediates efficient knockdown of Stat3, suppresses Stat3 activity and limits cell growth in murine (Tu2449) and human (U87, Mz18) glioma cells in vitro. In a therapeutic setting, intracranial application of the siRNA-containing LPP leads to knockdown of STAT3 target gene expression, decreased tumor growth and significantly prolonged survival in Tu2449 glioma-bearing mice compared to negative control-treated animals. This is a proof-of-concept study introducing PEI-based lipopolyplexes as an efficient strategy for therapeutically targeting oncoproteins with otherwise limited druggability. Full article
(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)
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Open AccessArticle Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma
Cancers 2019, 11(2), 248; https://doi.org/10.3390/cancers11020248
Received: 10 January 2019 / Revised: 4 February 2019 / Accepted: 14 February 2019 / Published: 20 February 2019
PDF Full-text (2570 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
STAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our [...] Read more.
STAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our group had previously packaged STAT3 inhibitors using a novel formulation of nanoparticles (NP) and found encouraging results. In this study, we aimed to further improve the pharmacologic properties of these NP by decorating them with monoclonal anti-CD38 antibodies. NP loaded with S3I-1757 (a STAT3 inhibitor), labeled as S3I-NP, were generated. S3I-NP decorated with anti-CD38 (labeled as CD38-S3I-NP) were found to have a similar nanoparticular size, drug encapsulation, and loading as S3I-NP. The release of S3I-1757 at 24 h was also similar between the two formulations. Using Cy5.5 labeling of the NP, we found that the decoration of anti-CD38 on these NP significantly increased the cellular uptake by two MM cell lines (p < 0.001). Accordingly, CD38-S3I-NP showed a significantly lower inhibitory concentration at 50% (IC50) compared to S3I-NP in two IL6-stimulated MM cell lines (p < 0.001). In a xenograft mouse model, CD38-S3I-NP significantly reduced the tumor size by 4-fold compared to S3I-NP on day 12 after drug administration (p = 0.006). The efficacy of CD38-S3I-NP in suppressing STAT3 phosphorylation in the xenografts was confirmed by using immunocytochemistry and Western blot analysis. In conclusion, our study suggests that the decoration of anti-CD38 on NP loaded with STAT3 inhibitors can further improve their therapeutic effects against MM. Full article
(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)
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