Author: Agerer, Franziska ; Waak, Jens ; Hennemann, Hanjo ; Schulten-Schulz, Carmen ; Vollmer, Jörg ; Meuser, Elena ; Ross, Katharina ; Arndt, Verena ; Friedrich, Daniel ; Friebe, Annette

AbstractDirect targeting of several important cancer pathways has so far proved challenging, owing to the lack of pathway-specific targets that can be accessed by conventional small molecule drugs or therapeutic antibodies. Nexigen develops and advances peptide-based cancer therapeutics, a new class of drugs that functionally modulate currently undruggable pathways by targeting intracellular protein-protein-interactions.One of these undruggable pathways, the Wnt signaling cascade, has been identified as a key pathway in cancer stem cells maintenance. Targeting oncongenic Wnt signaling therefore holds great promise for tackling not only tumor growth but also disease relapse, metastasis and drug resistance. Using our proprietary next generation peptide screening system, we could identify cell-permeable peptides that efficiently inhibit the Wnt pathway through a specific interaction with a key component of intracellular signaling. Our most advanced preclinical candidate has nanomolar target affinity and significantly reduces the expression of Wnt target genes in triple-negative MDA-MB-231 breast cancer cells. The further functional analysis of the peptide in various cancer cell lines revealed a dose-dependent inhibition of cell migration, invasion, proliferation, and the cancer stem cell phenotype. The siRNA-mediated knock-down of the target protein or the inhibition of the Wnt pathway recapitulated the inhibitory peptide effect in these assays. Most importantly, we observed a significant suppression of primary tumor growth, tumor cell self-renewal and a reduction of metastatic potential after treatment in different xenograft models.In summary, our data suggest that our Wnt pathway peptide inhibitor could be a promising new drug candidate for the treatment of cancer stem cells in a broad diversity of cancers.Citation Format: Verena Arndt, Annette Friebe, Elena Meuser, Katharina Ross, Franziska Agerer, Carmen Schulten-Schulz, Jens Waak, Daniel Friedrich, Hanjo Hennemann, Jörg Vollmer. Targeting cancer stem cell pathways with cell-permeable peptide inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2646. doi:10.1158/1538-7445.AM2015-2646

22 Apr 2013·Journal of Leukocyte BiologyQ3 · MEDICINE

Identification of novel oligonucleotides from mitochondrial DNA that spontaneously induce plasmacytoid dendritic cell activation

Q3 · MEDICINE

Article

Author: Ries, Moritz ; Schmidt, Barbara ; Donhauser, Norbert ; Schuster, Philipp ; Thomann, Sabrina ; Vollmer, Jörg

ABSTRACTThis study tested the hypothesis that mtDNA fragments carry immunostimulatory motifs that naturally induce immune activation by PDC. Genomic and mtDNA induced similar IFN-α production after transfection into PBMCs using the liposomal transfection reagent DOTAP. Shortening of mtDNA to CpG islands enhanced the immunostimulatory activity, based on the presence of unmethylated CpG DNA. Further fragmentation into mtODN, which exhibited similarities to published CpG ODN, resulted in a strong immunostimulatory activity in addition to PDC maturation and migration. The addition of the human cathelicidin LL-37 to CpG islands induced spontaneous PDC IFN-α production. Notably, one phosphodiester mtODN with a double-palindromic structure induced PDC IFN-α production in the absence of DOTAP. Flow cytometry, life-cell, and confocal imaging revealed attachment and spontaneous uptake into PDC, colocalizing, in part, with TLR9 in early endosomal vesicles. This process was accompanied by a moderate but significant PDC maturation in addition to B cell and NK cell activation (P<0.05). Altogether, our data indicate that fragmented mtDNA, which may be released as a consequence of apoptotic, necrotic, and necroptotic cell death, can act as a DAMP. For the first time, our study provides a mechanism how longer and shorter mtDNA fragments can be taken up naturally by the PDC and thus, may contribute to acute and chronic immune activation.

PLOS ONEQ3 · CROSS-FIELD

Guanine-Modified Inhibitory Oligonucleotides Efficiently Impair TLR7- and TLR9-Mediated Immune Responses of Human Immune Cells

Q3 · CROSS-FIELD

ArticleOA

Author: Uhlmann, Eugen ; Müller, Tina ; Miethke, Thomas ; Wagner, Hermann ; Waldhuber, Anna ; Römmler, Franziska ; Jurk, Marion ; Vollmer, Jörg ; Hammel, Monika

Activation of TLR7 and TLR9 by endogenous RNA- or DNA-containing ligands, respectively, is thought to contribute to the complicated pathophysiology of systemic lupus erythematosus (SLE). These ligands induce the release of type-I interferons by plasmacytoid dendritic cells and autoreactive antibodies by B-cells, both responses being key events in perpetuating SLE. We recently described the development of inhibitory oligonucleotides (INH-ODN), which are characterized by a phosphorothioate backbone, a CC(T)XXX3-5GGG motif and a chemical modification of the G-quartet to avoid the formation of higher order structures via intermolecular G-tetrads. These INH-ODNs were equally or significantly more efficient to impair TLR7- and TLR9-stimulated murine B-cells, macrophages, conventional and plasmacytoid dendritic cells than the parent INH-ODN 2088, which lacks G-modification. Here, we evaluate the inhibitory/therapeutic potential of our set of G-modified INH-ODN on human immune cells. We report the novel finding that G-modified INH-ODNs efficiently inhibited the release of IFN-α by PBMC stimulated either with the TLR7-ligand oligoribonucleotide (ORN) 22075 or the TLR9-ligand CpG-ODN 2216. G-modification of INH-ODNs significantly improved inhibition of IL-6 release by PBMCs and purified human B-cells stimulated with the TLR7-ligand imiquimod or the TLR9-ligand CpG-ODN 2006. Furthermore, inhibition of B-cell activation analyzed by expression of activation markers and intracellular ATP content was significantly improved by G-modification. As observed with murine B-cells, high concentrations of INH-ODN 2088 but not of G-modified INH-ODNs stimulated IL-6 secretion by PBMCs in the absence of TLR-ligands thus limiting its blocking efficacy. In summary, G-modification of INH-ODNs improved their ability to impair TLR7- and TLR9-mediated signaling in those human immune cells which are considered as crucial in the pathophysiology of SLE.

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