Therapeutic Targeting of Stat3 Using Lipopolyplex Nanoparticle-Formulated siRNA in a Syngeneic Orthotopic Mouse Glioma Model

Linder, Benedikt; Weirauch, Ulrike; Ewe, Alexander; Uhmann, Anja; Seifert, Volker; Mittelbronn, Michel; Harter, Patrick N.; Aigner, Achim; Kögel, Donat

doi:10.3390/cancers11030333

Cited by 24 publications

(27 citation statements)

References 70 publications

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“…This tumor inhibitory and tumor microenvironment normalizing effects of pacritinib could be attributed to the suppression of STAT3/JAK2 signaling. Our observations were supported by a recent report that the inhibition of JAK/STAT3 pathway resulted in the disrupted intercellular communications between microglia and GBM cells [35] and pronounced anti-GBM effects [36,37]. In addition, we found that pacritinib treatment was able to suppress the number of miR-21-enriched exosomes secreted by GAMs.…”

Section: Discussionsupporting

confidence: 90%

Preclinical Evidence of STAT3 Inhibitor, Pacritinib, Overcomes Temozolomide Resistance via Down-Regulating miR-21-enriched Exosomes from M2 Glioblastoma-Associated Macrophages

Chuang¹,

Su²,

Liu³

et al. 2019

Preprint

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Background: Tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). The dysfunctional TME promotes drug resistance, disease recurrence and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within TME may promote oncogenic phenotypes via transferring signaling molecules such as cytokines, proteins and microRNAs. Results: In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (GAMs) secreted exosomes which were enriched with oncomiR-21. Co-culture of GAMs (and GAM derived exosomes) and GBM cell lines resulted in the increased GBM cells’ resistance against temozolomide (TMZ) by upregulating pro-survival gene, PDCD4 and stemness markers Sox2, STAT3, Nestin and miR-21-5p and increased M2 cytokines, IL-6 and TGF-β1 secreted by GBM cells, promoting the M2 polarization of GAMs. Subsequently, pacritinib treatment suppressed GBM tumorigenesis and stemness; more importantly, pacritinib-treated GBM cells showed markedly reduced ability to secret M2 cytokines and reduced miR-21 enriched exosomes secreted by GAMs. Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which tumor suppressor PDCD4 was targeted. We subsequently established a patient-derived xenograft models where mice bore patient GBM and GAMs. The treatment of pacritinib, and the combination of pacritinib/TMZ appeared to significantly reduce tumorigenesis of GBM/GAM PDX mice, overcome TMZ-resistance, and M2 polarization of GAMs. Conclusion: In summation, we showed that potential of pacritinib alone or in combination with TMZ for suppressing GBM tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting pacritinib for the treatment of TMZ-resistant GBM in the clinical settings.

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Section: Discussionsupporting

confidence: 90%

Preclinical Evidence of STAT3 Inhibitor, Pacritinib, Overcomes Temozolomide Resistance via Down-Regulating miR-21-enriched Exosomes from M2 Glioblastoma-Associated Macrophages

Chuang¹,

Su²,

Liu³

et al. 2019

Preprint

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“…Complex sizes in the range of ~ 130 nm, an irregular shape of the complexes, as visualized by TEM, and a positive zeta potential of ~ 28 mV, as determined by Phase Analysis Light Scattering (PALS; Fig. 2 c, right), were very similar to previously described PEI/siRNA complexes (see e.g., [ 39 , 40 ]). Concomitantly, efficient uptake of PEI/antimiR complexes containing Cy3-labeled antimiRs was observed.…”

Section: Resultssupporting

confidence: 81%

Nanoparticle-complexed antimiRs for inhibiting tumor growth and metastasis in prostate carcinoma and melanoma

et al. 2020

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Background MiRNAs act as negative regulators of gene expression through target mRNA degradation or inhibition of its translation. In cancer, several miRNAs are upregulated and play crucial roles in tumorigenesis, making the inhibition of these oncomiRs an interesting therapeutic approach. This can be achieved by directly complementary single-stranded anti-miRNA oligonucleotides (antimiRs). A major bottleneck in antimiR therapy, however, is their efficient delivery. The nanoparticle formation with polyethylenimine (PEI) may be particularly promising, based on the PEI’s ability to electrostatically interact with oligonucleotides. This leads to their protection and supports delivery. In the present study, we explore for the first time PEI for antimiR formulation and delivery. We use the branched low molecular weight PEI F25-LMW for the complexation of different antimiRs, and analyse tumor- and metastasis-inhibitory effects of PEI/antimiR complexes in different tumor models. Results In prostate carcinoma, transfection of antimiRs against miR-375 and miR-141 leads to tumor cell inhibition in 2D- and 3D-models. More importantly, an in vivo tumor therapy study in prostate carcinoma xenografts reveals anti-tumor effects of the PEI/antimiR complexes. In advanced melanoma and metastasis, we identify by a microRNA screen miR-150 as a particularly relevant oncomiR candidate, and validate this result in vitro and in vivo. Again, the systemic application of PEI/antimiR complexes inhibiting this miRNA, or the previously described antimiR-638, leads to profound tumor growth inhibition. These effects are associated with the upregulation of direct miRNA target genes. In a melanoma metastasis mouse model, anti-metastatic effects of PEI/antimiR treatment are observed as well. Conclusions We thus describe PEI-based complexes as efficient platform for antimiR therapy, as determined in two different tumor entities using in vivo models of tumor growth or metastasis. Our study also highlights the therapeutic relevance of miR-375, miR-141, miR-150 and miR-638 as target miRNAs for antimiR-mediated inhibition.

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“…For breast cancer-based models, STAT3 was identified to promote PDL-1 expression, leading to reduced immune responses, which was validated through gene silencing and pharmacologic inhibition [34]. Direct targeting nanomedicine-based approaches were also applied in syngeneic glioblastoma mouse models, where lipid-formulated siRNA was capable of suppressing STAT3 activity and tumor growth [35]. STAT3 activation was also explored in hepatocellular carcinoma (HCC) arising from hepatitis C infections.…”

Section: Chapter 2: Targeting Stat3/5 In Solid Cancersmentioning

confidence: 99%

Targeting STAT3 and STAT5 in Cancer

Araujo

Keserü

Gunning

et al. 2020

Cancers

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Therapeutic Targeting of Stat3 Using Lipopolyplex Nanoparticle-Formulated siRNA in a Syngeneic Orthotopic Mouse Glioma Model

Cited by 24 publications

References 70 publications

Preclinical Evidence of STAT3 Inhibitor, Pacritinib, Overcomes Temozolomide Resistance via Down-Regulating miR-21-enriched Exosomes from M2 Glioblastoma-Associated Macrophages

Preclinical Evidence of STAT3 Inhibitor, Pacritinib, Overcomes Temozolomide Resistance via Down-Regulating miR-21-enriched Exosomes from M2 Glioblastoma-Associated Macrophages

Nanoparticle-complexed antimiRs for inhibiting tumor growth and metastasis in prostate carcinoma and melanoma

Targeting STAT3 and STAT5 in Cancer

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