RNA-targeted therapeutics in cancer clinical trials: Current status and future directions

Barata, Pedro C.; Sood, Anil K.; Hong, David S.

doi:10.1016/j.ctrv.2016.08.004

Cited by 136 publications

(101 citation statements)

References 148 publications

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“…siRNA-based therapeutics7, 8, 9, 10, 11 have shown promise for treating genetic diseases (e.g., transthyretin amyloidosis, hemophilia, and porphyria), metabolic diseases (e.g., hypercholesterolemia), virus infection diseases (hepatitis B virus [HBV], Ebola, HIV, and RSV [respiratory syncytial virus]), ophthalmic diseases (non-arteritic anterior ischemic optic neuropathy [NAION], age-related macular degeneration [AMD], and diabetic macular edema [DME]), and various solid tumors (e.g., hepatocellular carcinoma, melanoma, and pancreatic cancer). siRNA therapeutics for oncology that have entered clinical trials include ALN-KSP, CALAA-01, TKM-PLK1, Atu027, DCR-MYC, SiG12D-LODER, and siRNA-EPHA2-DOPC 12 . In addition, siRNA has been used to circumvent multiple drug resistance (MDR), to enhance the chemosensitivity of tumor cells to chemotherapeutics 13, 14, 15, 16.…”

Section: Introductionmentioning

confidence: 99%

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

Zheng

Wang

Weng

et al. 2018

Molecular Therapy - Nucleic Acids

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Pancreatic cancer is currently one of the deadliest of the solid malignancies, whose incidence and death rates are increasing consistently during the past 30 years. Ribonucleotide reductase (RR) is a rate-limiting enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides, which are essential for DNA synthesis and replication. In this study, 23 small interfering RNAs (siRNAs) against RRM2, the second subunit of RR, were designed and screened, and one of them (termed siRRM2), with high potency and good RNase-resistant capability, was selected. Transfection of siRRM2 into PANC-1, a pancreatic cell line, dramatically repressed the formation of cell colonies by inducing remarkable cell-cycle arrest at S-phase. When combining with doxorubicin (DOX), siRRM2 improved the efficacy 4 times more than applying DOX alone, suggesting a synergistic effect of siRRM2 and DOX. Moreover, the combined application of siRRM2-loaded lipid nanoparticle and DOX significantly suppressed the tumor growth on the PANC-1 xenografted murine model. The inhibition efficiency revealed by tumor weight at the endpoint of the treatment reached more than 40%. Hence, siRRM2 effectively suppressed pancreatic tumor growth alone or synergistically with DOX. This study provides a feasible target gene, a drug-viable siRNA, and a promising therapeutic potential for the treatment of pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

Zheng

Wang

Weng

et al. 2018

Molecular Therapy - Nucleic Acids

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“…With advancement in the technologies for administration of miRNA, miRNA therapy becomes a real option for the management of various diseases787980. Therapeutics using miR-155 inhibitors have also been developed for lung cancer81.…”

Section: Discussionmentioning

confidence: 99%

Inflammation-induced miRNA-155 inhibits self-renewal of neural stem cells via suppression of CCAAT/enhancer binding protein β (C/EBPβ) expression

Obora

Onodera

Takehara

et al. 2017

Sci Rep

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Intracerebral inflammation resulting from injury or disease is implicated in disruption of neural regeneration and may lead to irreversible neuronal dysfunction. Analysis of inflammation-related microRNA profiles in various tissues, including the brain, has identified miR-155 among the most prominent miRNAs linked to inflammation. Here, we hypothesize that miR-155 mediates inflammation-induced suppression of neural stem cell (NSC) self-renewal. Using primary mouse NSCs and human NSCs derived from induced pluripotent stem (iPS) cells, we demonstrate that three important genes involved in NSC self-renewal (Msi1, Hes1 and Bmi1) are suppressed by miR-155. We also demonstrate that suppression of self-renewal genes is mediated by the common transcription factor C/EBPβ, which is a direct target of miR-155. Our study describes an axis linking inflammation and miR-155 to expression of genes related to NSC self-renewal, suggesting that regulation of miR-155 may hold potential as a novel therapeutic strategy for treating neuroinflammatory diseases.

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“…Finally, recent progress in cell transfection techniques has led to development of efficient formulations for therapeutic delivery of synthetic microRNAs based on cationic polymers or exosomes [58, 59]. These techniques have made the use of small RNAs in human therapy a promising therapeutic approach and several clinical trials are in progress [60]. …”

Section: Discussionmentioning

confidence: 99%

Lowered expression of microRNA-125a-5p in human hepatocellular carcinoma and up-regulation of its oncogenic targets sirtuin-7, matrix metalloproteinase-11, and c-Raf

Coppola

Stefano

Panella³

et al. 2017

Oncotarget

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Human microRNA-125a-5p (miR-125a) is expressed in most tissues where it downregulates the expression of membrane receptors or intracellular transductors of mitogenic signals, thus limiting cell proliferation. Expression of this miRNA generally increases with cell differentiation whereas it is downregulated in several types of tumors, such as breast, lung, ovarian, gastric, colon, and cervical cancers, neuroblastoma, medulloblastoma, glioblastoma, and retinoblastoma. In this study, we focused on hepatocellular carcinoma and used real-time quantitative PCR to measure miR-125a expression in 55 tumor biopsies and in matched adjacent non-tumor liver tissues. This analysis showed a downregulation of miR-125a in 80 % of patients, with a mean decrease of 4.7-fold. Comparison of miRNA downregulation with clinicopathological parameters of patients didn't yield significant correlations except for serum bilirubin. We then evaluated the expression of known targets of miR-125a and found that sirtuin-7, matrix metalloproteinase-11, and c-Raf were up-regulated in tumor tissue by 2.2-, 3-, and 1.7-fold, respectively. Overall, these data support a tumor suppressor role for miR-125a and encourage further studies aimed at the comprehension of the molecular mechanisms governing its expression, eventually leading to treatments to restore its expression in tumor cells.

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RNA-targeted therapeutics in cancer clinical trials: Current status and future directions

Cited by 136 publications

References 148 publications

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

Inflammation-induced miRNA-155 inhibits self-renewal of neural stem cells via suppression of CCAAT/enhancer binding protein β (C/EBPβ) expression

Lowered expression of microRNA-125a-5p in human hepatocellular carcinoma and up-regulation of its oncogenic targets sirtuin-7, matrix metalloproteinase-11, and c-Raf

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