Lipid Nanoparticle–Mediated Delivery of Anti-miR-17 Family Oligonucleotide Suppresses Hepatocellular Carcinoma Growth

Huang, Xinqiang; Magnus, Jill; Kaimal, Vivek; Karmali, Priya; Li, Jian; Walls, Marlena; Prudente, Rene; Sung, Eric; Sorourian, Mehran; Lee, Robin; Davis, Scott; Xia, Yang; Estrella, Heather; Lee, Edmund C.; Chau, B. Nelson; Pavlı́ček, Adam; Zabludoff, Sonya

doi:10.1158/1535-7163.mct-16-0613

Cited by 20 publications

(17 citation statements)

References 43 publications

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“…Anti-miR-17 therapy was examined in an autochthonous transgenic mouse model of MYC-driven HCC ( LAP-tTA/tet-O-MYC ) [ 17 ]. A lipid nanoparticle (LNP) encapsulating anti-miR-17 family oligonucleotide was utilized, as has been described previously (RL01-17(5))[ 15 ]. In LAP-tTA/tet-O-MYC transgenic mice MYC expression was induced at 4 weeks after birth leading to tumorigenesis.…”

Section: Resultsmentioning

confidence: 99%

“…We hypothesized that targeting miR-17 could be effective strategy for MYC driven cancers. Cell-line based studies have shown that targeting miR-17 can suppress tumor proliferation [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, several challenges exist in achieving drug stability and ensuring tissue-specific drug delivery [ 13 , 14 ]. Recently, a novel approach for targeting miR-17 with a tough decoy (TuD) antisense miR17 delivered via systemic lipid nanoparticle (LNP) has been shown to be effective in HCC cell lines [ 15 ]. We have evaluated the feasibility of liver-specific anti-miR delivery to achieve sustained target de-repression in the liver tumor without general liver toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC)

et al. 2017

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Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options. Genomic amplification and/or overexpression of the MYC oncogene is a common molecular event in HCC, thus making it an attractive target for drug therapy. Unfortunately, currently there are no direct drug therapies against MYC. As an alternative strategy, microRNAs regulated by MYC may be downstream targets for therapeutic blockade. MiR-17 family is a microRNA family transcriptionally regulated by MYC and it is commonly overexpressed in human HCCs. In this study, we performed systemic delivery of a novel lipid nanoparticle (LNP) encapsulating an anti-miR-17 oligonucleotide in a conditional transgenic mouse model of MYC driven HCC. Treatment with anti-miR-17 in vivo, but not with a control anti-miRNA, resulted in significant de-repression of direct targets of miR-17, robust apoptosis, decreased proliferation and led to delayed tumorigenesis in MYC-driven HCCs. Global gene expression profiling revealed engagement of miR-17 target genes and inhibition of key transcriptional programs of MYC, including cell cycle progression and proliferation. Hence, anti-miR-17 is an effective therapy for MYC-driven HCC.

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Section: Resultsmentioning

confidence: 99%

“…We hypothesized that targeting miR-17 could be effective strategy for MYC driven cancers. Cell-line based studies have shown that targeting miR-17 can suppress tumor proliferation [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC)

et al. 2017

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“…Huang et al delivered antimiR-17 with a lipid NP. MiR-17 is an oncogene, and ectopic expression with miR-17-3p results in the development of HCC in a mouse model [129,130]. The suppression of this oncogene through antimiR-17 delivery hindered the proliferation of HCC cells.…”

Section: Mirnasmentioning

confidence: 99%

Liver Cancer: Current and Future Trends Using Biomaterials

Chew

Moscato

George

et al. 2019

Cancers

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Hepatocellular carcinoma (HCC) is the fifth most common type of cancer diagnosed and the second leading cause of death worldwide. Despite advancement in current treatments for HCC, the prognosis for this cancer is still unfavorable. This comprehensive review article focuses on all the current technology that applies biomaterials to treat and study liver cancer, thus showing the versatility of biomaterials to be used as smart tools in this complex pathologic scenario. Specifically, after introducing the liver anatomy and pathology by focusing on the available treatments for HCC, this review summarizes the current biomaterial-based approaches for systemic delivery and implantable tools for locally administrating bioactive factors and provides a comprehensive discussion of the specific therapies and targeting agents to efficiently deliver those factors. This review also highlights the novel application of biomaterials to study HCC, which includes hydrogels and scaffolds to tissue engineer 3D in vitro models representative of the tumor environment. Such models will serve to better understand the tumor biology and investigate new therapies for HCC. Special focus is given to innovative approaches, e.g., combined delivery therapies, and to alternative approaches—e.g., cell capture—as promising future trends in the application of biomaterials to treat HCC.

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“…15 Based on this work there has been a growing interest in developing anti-miR drugs designed to target the miR-17~92 cluster. [16][17][18][19][20][21] miR-17~92, however, is a complex polycistronic cluster that encodes 6 individual miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a-1). Moreover, the mammalian genome encodes two additional paralogous clusters known as miR-106a~363 and miR-106b~25.…”

Section: Introductionmentioning

confidence: 99%

Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth

Yheskel

Lakhia

Flaten

et al. 2018

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of renal failure. We have recently shown that inhibiting miR-17~92 is a potential novel therapeutic approach for ADPKD. However, miR-17~92 is a polycistronic cluster that encodes microRNAs (miRNAs) belonging to the miR-17, miR-18, miR-19 and miR-25 families, and the relative pathogenic contribution of these miRNA families to ADPKD progression is unknown. Here we performed an in vivo anti-miR screen to identify the miRNA drug targets within the miR-17~92 miRNA cluster. We designed anti-miRs to individually inhibit miR-17, miR-18, miR-19 or miR-25 families in an orthologous ADPKD model. Treatment with anti-miRs against the miR-17 family reduced cyst proliferation, kidney-weight-to-body-weight ratio and cyst index. In contrast, treatment with anti-miRs against the miR-18, 19, or 25 families did not affect cyst growth. Anti-miR-17 treatment recapitulated the gene expression pattern observed after miR-17~92 genetic deletion and was associated with upregulation of mitochondrial metabolism, suppression of the mTOR pathway, induction of autophagy, and inhibition of cyst-associated inflammation. Our results argue against functional cooperation between the various miR-17~92 cluster families in promoting cyst growth, and instead point to miR-17 family is the primary therapeutic target for ADPKD. driver of kidney cyst growth

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Lipid Nanoparticle–Mediated Delivery of Anti-miR-17 Family Oligonucleotide Suppresses Hepatocellular Carcinoma Growth

Cited by 20 publications

References 43 publications

Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC)

Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC)

Liver Cancer: Current and Future Trends Using Biomaterials

Anti-microRNA screen uncovers miR-17 family within miR-17~92 cluster as the primary driver of kidney cyst growth

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