Sustained suppression of Bcr-Abl-driven lymphoid leukemia by microRNA mimics

McLaughlin, Jami; Cheng, Donghui; Singer, Oded; Lukacs, Rita U.; Radu, Caius G.; Verma, Inder M.; Witte, Owen N.

doi:10.1073/pnas.0710532105

Cited by 59 publications

(36 citation statements)

References 64 publications

(74 reference statements)

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“…63 Also, tandem arrays of miRNA mimics delivered by lentiviral vectors proved effective against Bcr --Abl lymphoid leukemia. 64 Although the multispecific nature of miRNAs makes them very effective in regulating cellular processes associated with normal cell function and neoplastic development, this property can also be a weakness of miRNA-based therapy, as perturbing miRNA levels may affect the expression of unintended mRNA target. Another major concern would be that the introduction of exogenous miRNAs may overwhelm the RNAinduced silencing complex and inhibit the processing of other miRNAs that are involved in normal cellular function.…”

Section: Mirnas As Therapeutic Agents---breakthroughs and Challengesmentioning

confidence: 99%

MicroRNAs in prostate cancer: from biomarkers to molecularly-based therapeutics

Gordanpour

Nam

Sugar

et al. 2012

Prostate Cancer Prostatic Dis

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MicroRNAs (miRNAs) are effective regulators of gene expression that have a significant role in the pathogenesis of prostate and various other cancers. The high prevalence of aberrant miRNA expression in prostate cancer, and miRNAs' distinctive properties, give much hope that they can be used as biomarkers and next generation of molecular anticancer therapeutics. Herein, we review the literature on miRNA involvement in prostate cancer pathogenesis and the current understanding of their role as oncogenes, tumor suppressors and metastasis-regulators. We also review the latest research on miRNAs in prostate cancer preclinical studies and clinical trials, and highlight the advantages and challenges of possible miRNA-based therapies. The emerging information regarding the biology of miRNAs in prostate cancer is promising, and may lead to a role(s) for these molecules as diagnostic/prognostic markers and effective therapeutic tools for better molecularly targeted treatment of prostate cancer.

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Section: Mirnas As Therapeutic Agents---breakthroughs and Challengesmentioning

confidence: 99%

MicroRNAs in prostate cancer: from biomarkers to molecularly-based therapeutics

Gordanpour

Nam

Sugar

et al. 2012

Prostate Cancer Prostatic Dis

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“…However, any design criteria for such an siRNA based therapy will need to account for the extremely high levels of activity typically characteristic of fusion oncogenes. Even trace amounts of these dangerous chimeric proteins may be sufficient to drive aberrant growth (8).…”

mentioning

confidence: 99%

Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence

Gavrilov

Seo

Tietjen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Canonical siRNA design algorithms have become remarkably effective at predicting favorable binding regions within a target mRNA, but in some cases (e.g., a fusion junction site) region choice is restricted. In these instances, alternative approaches are necessary to obtain a highly potent silencing molecule. Here we focus on strategies for rational optimization of two siRNAs that target the junction sites of fusion oncogenes BCR-ABL and TMPRSS2-ERG. We demonstrate that modifying the termini of these siRNAs with a terminal G-U wobble pair or a carefully selected pair of terminal asymmetry-enhancing mismatches can result in an increase in potency at low doses. Importantly, we observed that improvements in silencing at the mRNA level do not necessarily translate to reductions in protein level and/or cell death. Decline in protein level is also heavily influenced by targeted protein half-life, and delivery vehicle toxicity can confound measures of cell death due to silencing. Therefore, for BCR-ABL, which has a long protein halflife that is difficult to overcome using siRNA, we also developed a nontoxic transfection vector: poly(lactic-coglycolic acid) nanoparticles that release siRNA over many days. We show that this system can achieve effective killing of leukemic cells. These findings provide insights into the implications of siRNA sequence for potency and suggest strategies for the design of more effective therapeutic siRNA molecules. Furthermore, this work points to the importance of integrating studies of siRNA design and delivery, while heeding and addressing potential limitations such as restricted targetable mRNA regions, long protein half-lives, and nonspecific toxicities.drug delivery | RNA interference | leukemia | BCR-Abl | TMPRSS2-ERG

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“…In fact, a recent study demonstrated that an array of miRNAs (although not a single miRNA sequence) could be used to inhibit the BCR-ABL oncogene implicated in leukemia [89]. It is also possible to use antisense oligonucleotides to knockdown expression of miRNAs, inhibiting their function in vivo.…”

Section: Rna Interferencementioning

confidence: 99%

Antisense, RNAi, and gene silencing strategies for therapy: Mission possible or impossible?

Rayburn

Zhang

2008

Drug Discovery Today

157

115

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Antisense oligonucleotides can regulate gene expression in living cells. As such, they regulate cell function and division, and can modulate cellular responses to internal and external stresses and stimuli. Although encouraging results from preclinical and clinical studies have been obtained and significant progress has been made in developing these agents as drugs, they are not yet recognized as effective therapeutics. Several major hurdles remain to be overcome, including problems with efficacy, off-target effects, delivery and side effects. The lessons learned from antisense drug development can help in the development of other oligonucleotide-based therapeutics such as CpG oligonucleotides, RNAi and miRNA. KeywordsAntisense; RNAi; Drug targeting; cancer; chemotherapy Historical perspectiveThe development of the antisense approach started in the late 1970s after the discovery that the expression of a specific gene product could be inhibited using a short complementary DNA sequence [1]. Since then, the antisense strategy has enjoyed exponential gains in interest and has been the subject of more than 16,000 publications. Between the appearance of the first publication about the antisense strategy in 1978 and the beginning of intensive antisense research (commencing in the early 1990s) very few studies were published. The increase in antisense research was largely a result of improvements in the methods used for DNA sequencing and synthesizing oligonucleotides [2,3]. Other major milestones in the development of antisense strategies include numerous discoveries about antisense chemistry. The most notable discovery was the addition of a phosphorothioate backbone to the *Correspondence and request for reprints to:

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Sustained suppression of Bcr-Abl-driven lymphoid leukemia by microRNA mimics

Cited by 59 publications

References 64 publications

MicroRNAs in prostate cancer: from biomarkers to molecularly-based therapeutics

MicroRNAs in prostate cancer: from biomarkers to molecularly-based therapeutics

Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence

Antisense, RNAi, and gene silencing strategies for therapy: Mission possible or impossible?

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