Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer

Voutila, Jon; Reebye, Vikash; Roberts, Thomas C.; Protopapa, Pantelitsa; Andrikakou, Pinelopi; Blakey, David C.; Habib, Robert; Huber, Hans E.; Sætrom, Pål; Rossi, John J.; Habib, Nagy

doi:10.1016/j.ymthe.2017.07.018

Cited by 79 publications

(78 citation statements)

References 34 publications

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“…Searching for molecular mechanisms, we found that stabilization of key regulators of liver biology (C/EBPα, HNF4α, CUGBP1, Rb, and p53) under conditions of an HFD contributes to inhibition of steatosis. In agreement with this, several reports from Habib's group showed that the elevation of C/EBPα by a short‐activating RNA causes inhibition of liver cancer, metastasis, cirrhosis, fibrosis, and hepatosteatosis . In agreement with these observations, HFD‐treated GLKO mice and C/EBPα‐S193A mice have reduced C/EBPα and increased proliferation and spontaneously develop fibrosis and HCC, a situation observed in CUGBP1‐S302A mice.…”

Section: Discussionsupporting

confidence: 76%

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) involves development of hepatic steatosis, fibrosis, and steatohepatitis. Because hepatic steatosis appears first in NAFLD animal models, the current therapy development focuses on inhibition of hepatic steatosis, suggesting that further steps of NAFLD will be also inhibited. In this report, we show that the first event of NAFLD is liver proliferation, which drives fibrosis in NAFLD. We have deleted a strong driver of liver proliferation, gankyrin (Gank), and examined development of NAFLD in this animal model under conditions of a high‐fat diet (HFD). We found that proliferating livers of wild‐type mice develop fibrosis; however, livers of Gank liver‐specific knockout (GLKO) mice with reduced proliferation show no fibrosis. Interestingly, an HFD causes the development of strong macrovesicular steatosis in GLKO mice and is surprisingly associated with improvements in animal health. We observed that key regulators of liver biology CCAAT/enhancer binding protein α (C/EBPα), hepatocyte nuclear factor 4α (HNF4α), p53, and CUG repeat binding protein 1 (CUGBP1) are elevated due to the deletion of Gank and that these proteins support liver functions leading to healthy conditions in GLKO mice under an HFD. To examine the role of one of these proteins in the protection of liver from fibrosis, we used CUGBP1‐S302A knockin mice, which have a reduction of CUGBP1 due to increased degradation of this mutant by Gank. These studies show that reduction of CUGBP1 inhibits steatosis and facilitates liver proliferation, leading to fibrosis and the development of liver tumors. Conclusion: Liver proliferation drives fibrosis, while steatosis might play a protective role. Therapy for NAFLD should include inhibition of proliferation rather than inhibition of steatosis.

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Section: Discussionsupporting

confidence: 76%

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

et al. 2019

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“…This saRNA activates the CEBPA mRNA and inhibits the growth of liver cancer cell lines in vitro. 97 Kim et al (2019) evaluated N-acetylgalactosamine (GalNAc) conjugation to antisense oligonucleotides (ASO) as a novel therapeutic approach that enhanced the antitumor activity in the HCC tumor model. ADP-ribosylation 4C (ARL4C) is a small GTP-binding protein that is highly expressed in primary HCC tumors.…”

Section: Strategies For Active Targeting To Livermentioning

confidence: 99%

<p>Nanocarrier-Based Therapeutics and Theranostics Drug Delivery Systems for Next Generation of Liver Cancer Nanodrug Modalities</p>

Ruman

Fakurazi

Masarudin

et al. 2020

IJN

110

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The development of therapeutics and theranostic nanodrug delivery systems have posed a challenging task for the current researchers due to the requirement of having various nanocarriers and active agents for better therapy, imaging, and controlled release of drugs efficiently in one platform. The conventional liver cancer chemotherapy has many negative effects such as multiple drug resistance (MDR), high clearance rate, severe side effects, unwanted drug distribution to the specific site of liver cancer and low concentration of drug that finally reaches liver cancer cells. Therefore, it is necessary to develop novel strategies and novel nanocarriers that will carry the drug molecules specific to the affected cancerous hepatocytes in an adequate amount and duration within the therapeutic window. Therapeutics and theranostic systems have advantages over conventional chemotherapy due to the high efficacy of drug loading or drug encapsulation efficiency, high cellular uptake, high drug release, and minimum side effects. These nanocarriers possess high drug accumulation in the tumor area while minimizing toxic effects on healthy tissues. This review focuses on the current research on nanocarrier-based therapeutics and theranostic drug delivery systems excluding the negative consequences of nanotechnology in the field of drug delivery systems. However, clinical developments of theranostics nanocarriers for liver cancer are considered outside of the scope of this article. This review discusses only the recent developments of nanocarrier-based drug delivery systems for liver cancer therapy and diagnosis. The negative consequences of individual nanocarrier in the drug delivery system will also not be covered in this review.

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“…C/EBPα saRNA (CEBPA-51): 30 sense, 5′-GCmG GmUC mAUmU GmUC mACmU GmGU CmUmU-3′ (special: 2′-OMe modified), and antisense, 5′-GAC CAG UGA CAA UGA CCG CmUmU-3′ (special: 2′-OMe modified 3′-UU overhang). Unrelated control siRNA: sense, 5′-GCG GAG ACA GCG ACG AAG AGC UCA UCA-3′, and antisense, 5′-UGA GCU CUU CGU CGC UGU CUC CGC UU-3′.…”

Section: Methodsmentioning

confidence: 99%

“…Previous mechanistic studies have suggested that such short double-stranded RNAs that specifically target the promoter region of a gene can activate its transcription, a phenomenon termed transcription gene activation (TGA) which involves Argonaute-2 protein (Ago-2) activity. 21 , 30 The clinical observations revealed that intravenous (i.v.) administration of MTL-CEBPA induced an increase in CEBPA mRNA in white blood cells (WBCs) and a doubling of neutrophils within 24 h of dosing.…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice

Zhou

Xia

et al. 2019

Molecular Therapy

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Excessive or inappropriate inflammatory responses can cause serious and even fatal diseases. The CCAAT/enhancer-binding protein alpha (CEBPA) gene encodes C/EBPα, a transcription factor that plays a fundamental role in controlling maturation of the myeloid lineage and is also expressed during the late phase of inflammatory responses when signs of inflammation are decreasing. MTL-CEBPA, a small activating RNA targeting for upregulation of C/EBPα, is currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. After dosing, subjects had reduced levels of pro-inflammatory cytokines , and we therefore hypothesized that MTL-CEBPA has anti-inflammatory potential. The current study was conducted to determine the effects of C/EBPα saRNA - CEBPA-51 - on inflammation in vitro and in vivo after endotoxin challenge. CEBPA-51 led to increased expression of the C/EBPα gene and inhibition of pro-inflammatory cytokines in THP-1 monocytes previously stimulated by E. coli -derived lipopolysaccharide (LPS). Treatment with MTL-CEBPA in an LPS-challenged humanized mouse model upregulated C/EBPα mRNA, increased neutrophils, and attenuated production of several key pro-inflammatory cytokines , including TNF-α, IL-6, IL-1β, and IFN - γ. In addition, a Luminex analysis of mouse serum revealed that MTL-CEBPA reduced pro-inflammatory cytokines and increased the anti-inflammatory cytokine IL-10. Collectively, the data support further investigation of MTL-CEBPA in acute and chronic inflammatory diseases where this mechanism has pathogenic importance.

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Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer

Cited by 79 publications

References 34 publications

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

<p>Nanocarrier-Based Therapeutics and Theranostics Drug Delivery Systems for Next Generation of Liver Cancer Nanodrug Modalities</p>

Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice

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