Therapeutic Efficacy of Bifunctional siRNA Combining TGF-β1 Silencing with RIG-I Activation in Pancreatic Cancer

Ellermeier, Jonathan; Wei, Jiwu; Duewell, Peter; Hoves, Sabine; Stieg, Mareike R.; Adunka, Tina; Noerenberg, Daniel; Anders, Hans‐Joachim; Mayr, Doris; Poeck, Hendrik; Hartmann, Gunther; Endres, Stefan; Schnurr, Max

doi:10.1158/0008-5472.can-11-3850

Cited by 131 publications

(165 citation statements)

References 36 publications

(37 reference statements)

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“…19,20 RLH ligands have been evaluated as therapeutic agents in preclinical tumor models for melanoma, ovarian cancer and pancreatic cancer. 19,[21][22][23][24] Therapeutic efficacy was enhanced by combining RNAi-mediated gene silencing with RIG-I activation in a single RNA molecule. 21,24 A ppp-siRNA targeting the anti-apoptotic protein Bcl-2 to promote tumor apoptosis showed therapeutic efficacy in experimental melanoma.…”

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confidence: 99%

“…19,[21][22][23][24] Therapeutic efficacy was enhanced by combining RNAi-mediated gene silencing with RIG-I activation in a single RNA molecule. 21,24 A ppp-siRNA targeting the anti-apoptotic protein Bcl-2 to promote tumor apoptosis showed therapeutic efficacy in experimental melanoma. 24 In this model, the antitumor effect was dependent on NK cells.…”

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confidence: 99%

“…To counteract tumor-induced immunosuppression, our group generated a ppp-siRNA silencing TGF-b1, which showed therapeutic efficacy in an orthotopic model of pancreatic cancer. 21 Interestingly, with this approach CD8 þ T cells mediated antitumor efficacy. Others reported that treatment of human ovarian cancer cells with RLH ligands resulted in phagocytosis of apoptotic tumor cells by monocyte-derived DCs and DC activation.…”

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confidence: 99%

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RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

et al. 2014

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Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8aþ DCs effectively engulfed apoptotic tumor material and cross-presented tumorassociated antigen to naive CD8 þ T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity.

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confidence: 99%

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RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

et al. 2014

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“…(2005) have already indicated the therapeutic potential of antagonizing the TGF-β pathway in gastrointestinal cancer. Combining RIG-I activation with TGF-β1 silencing via bifunctional ppp-siRNA breaks tumor-mediated immunosuppresive mechanisms and confers potent antitumor efficacy in pancreatic cancer (Ellermeier et al, 2013). The expression of TGF-β1 might be suppressed by Cantharidinate and then prevent the development of colorectal cancer (Jie Ma et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Protein Expression in Non-Small Cell Lung Cancers is Correlated with Prognosis

Huang¹,

Liu²,

Qi³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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To investigate the expression intensity and prognostic significance of TGF-β1 protein in non-small cell lung cancer (NSCLC), immunohistochemistry was carried out in 194 cases of NSCLC and 24 cases of normal lung tissues by SP methods. The PU (positive unit) value was used to assess the TGF-β1 protein expression in systematically selected fields under the microscope with Leica Q500MC image analysis. We found that the TGF-β1 PU value was nearly two-fold higher in NSCLC than in normal lung tissues (p=0.000), being associated with TNM stages (p=0.000) and lymph node metastases (p=0.000), but not to patient age, gender, smoking history, tumor differentiation, histological subtype and tumor location (P>0.05). Univariate analysis indicated that patients with high TGF-β1 protein expression and lymph node metastases demonstrated a poor prognosis (both p=0.000, ). Multivariate analysis showed that TGF-β1 protein expression (RR = 2.565, p=0.002) and lymph node metastases (RR=1.874, p= 0.030) were also independent prognostic factors. Thus, TGF-β1 protein expression may be correlated to oncogenesis and serve as an independent prognostic biomarker for NSCLC.

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“…These bifunctional molecules, linking potent gene silencing properties to suitable production of IFNs, can effectively control chronic viral diseases such as HIV-AIDS, HBV and HCV infections [95][96][97] . Furthermore, the application of this new siRNA design can not only overcome the cancer drug resistance, but also strengthen the immune surveillance usually evaded by cancer cells [98][99][100][101][102] …”

Section: Immunostimulationmentioning

confidence: 99%

siRNA and RNAi optimization

Alagia

Eritja

2016

WIREs RNA

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Abstract.The discovery and examination of the post-transcriptional gene regulatory mechanism known as RNA interference (RNAi), contributed to the identification of small interfering RNA (siRNA) and the comprehension of its enormous potential for clinical purposes. Theoretically, the ability of specific target gene downregulation makes the RNAi pathway an appealing solution for several diseases. Despite numerous hurdles resulting from the inherent properties of siRNA molecule and proper delivery to the target tissue, more than 50 RNA-based drugs are currently under clinical testing. In this work we analyze the recent literature in the optimization of siRNA molecules. In detail, we focused on describing the most recent advances of siRNA field aimed at optimize siRNA pharmacokinetic properties. Special attention has been given in describing the impact of RNA modifications in the potential off-target effects such as saturation of the RNAi machinery, passenger strand-mediated silencing, immunostimulation and miRNA-like off-target effects as well as to recent developments on the delivery issue. The novel delivery systems and modified siRNA provide significant steps towards the development of reliable siRNA molecules for therapeutic use.

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Therapeutic Efficacy of Bifunctional siRNA Combining TGF-β1 Silencing with RIG-I Activation in Pancreatic Cancer

Cited by 131 publications

References 36 publications

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

TGF-β1 Protein Expression in Non-Small Cell Lung Cancers is Correlated with Prognosis

siRNA and RNAi optimization

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