U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo

Goraczniak, Rafal; Wall, B.; Behlke, Mark A.; Lennox, Kim A.; Ho, Eric S.; Zaphiros, Nikolas; Jakubowski, Christopher; Patel, Neil; Zhao, Steven; Magaway, Carlo; Subbie, Stacey A; Yu, Lumeng J.; LaCava, Stephanie; Reuhl, Kenneth R.; Chen, Suzie; Gunderson, Samuel

doi:10.1038/mtna.2013.24

Cited by 5 publications

(9 citation statements)

References 58 publications

(89 reference statements)

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“…As a result of the tethering of the U1 snRNP to the target pre-mRNA, maturation is prevented and reduced levels of mature mRNA are produced [ 51 ]. To deliver the U1 Adaptors to the cells, we used a tumor-targeting dendrimer nanoparticle previously described [ 52 ]. The dendrimer nanoparticle, known as RGD-G5, contains the cyclic RGD pentapeptide, a tumor targeting ligand, which specifically binds the α5β3 splice variant of an integrin cell surface receptor overexpressed in a wide variety of cancer cells.…”

Section: Resultsmentioning

confidence: 99%

The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma

et al. 2016

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Receptor tyrosine kinases-based autocrine loops largely contribute to activate the MAPK and PI3K/AKT pathways in melanoma. However, the molecular mechanisms involved in generating these autocrine loops are still largely unknown. In the present study, we examine the role of the transcription factor RUNX2 in the regulation of receptor tyrosine kinase (RTK) expression in melanoma. We have demonstrated that RUNX2-deficient melanoma cells display a significant decrease in three receptor tyrosine kinases, EGFR, IGF-1R and PDGFRβ. In addition, we found co-expression of RUNX2 and another RTK, AXL, in both melanoma cells and melanoma patient samples. We observed a decrease in phosphoAKT2 (S474) and phosphoAKT (T308) levels when RUNX2 knock down resulted in significant RTK down regulation. Finally, we showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL in melanoma cells resistant to the BRAF V600E inhibitor PLX4720. Taken together, our results strongly suggest that RUNX2 might be a key player in RTK-based autocrine loops and a mediator of resistance to BRAF V600E inhibitors involving RTK up regulation in melanoma.

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Section: Resultsmentioning

confidence: 99%

The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma

et al. 2016

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“…1B). For further validation, a modified KRAS Adaptor (1B) containing five locked nucleic acid (LNA) modifications was evaluated in MIA PaCa-2 cells since LNAs are able to provide a “boost”, albeit unpredictable, in silencing activity (7). This was compared to siRNA, but also a control U1 Adaptor, which had a scrambled target domain (TD) (Supp.…”

Section: Resultsmentioning

confidence: 99%

“…To determine if the KRAS U1 Adaptors could inhibit pancreatic xenograft tumor growth, we evaluated the U1 KRAS3 adaptor using our previously validated formulation containing PAMAM dendrimers covalently linked to the cRGD peptide (7) (Fig. 2D, top).…”

Section: Resultsmentioning

confidence: 99%

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U1 Adaptors Suppress the KRAS-MYC Oncogenic Axis in Human Pancreatic Cancer Xenografts

Tsang

Dudgeon

Lan

et al. 2017

Molecular Cancer Therapeutics

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Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell lines in vitro and in vivo. As a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localization in vivo. Efficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) anti-tumor activity of both iRGD and (cRGD)2-KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused apoptosis in vitro (40–70%) and tumor regressions in vivo. Comparison of iRGD conjugated U1 KRAS and U1 MYC Adaptors in vivo revealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle free delivery system to target two undruggable genes in cancer.

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“…Inhibition of poly-A tail addition at PAS suppresses pre-mRNA maturation and induces target destabilization U1 adaptor and inhibits poly-A tail addition. Although the use of U1 Adaptors might lead to "off-target" silencing effects as a result of sequestration of endogenous U1 snRNP when used at high doses [ 44 ], recent results demonstrate that very low doses of two U1 Adaptors targeting BCL2 and GRM1 suppress growth of human melanoma xenografts in vivo with little toxicity [ 45 ].…”

Section: Other U1insmentioning

confidence: 99%

U1 interference (U1i) for Antiviral Approaches

Blázquez

Fortes

2015

Advances in Experimental Medicine and Biology

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U1 snRNP (U1 small nuclear ribonucleoprotein) is an essential component of the splicing machinery. U1 snRNP also plays an additional role in 3'-end mRNA processing when it binds close to polyadenylation sites (PAS). Cotranscriptionally, U1 snRNP binding close to putative PAS prevents premature cleavage and polyadenylation and consequently safeguards pre-mRNA transcripts and defines promoter directionality. At the 3'-end of mRNAs, U1 snRNP binding to putative PAS may regulate mRNA length or inhibit polyadenylation and, therefore, gene expression. U1 interference (U1i) is a technique to inhibit gene expression based on the property of U1 snRNP to inhibit polyadenylation. It requires the expression of a modified U1 snRNP, which interacts with a target gene upstream of its PAS and inhibits target gene expression. U1i has been used to inhibit the expression of reporter or endogenous genes both in tissue culture and in animal models. In addition, U1i combination with RNA interference (RNAi), another RNA-based gene silencing technology, results in a synergistic increased inhibition. This is of special interest for antiviral therapy, where strong inhibitions may be required to decrease the expression of replicative viral RNAs and impact the replication cycle. Furthermore, the combination of U1i and RNAi-based inhibitors should prevent the appearance of viral variants resistant to the treatment and allows the dose of inhibitors to be decreased and a functional inhibition to be obtained with fewer off target effects. In fact, U1i has been used to inhibit the expression of HIV-1 and HBV, whose viral genomes express mRNAs that must be polyadenylated by the nuclear polyadenylation machinery. In the case of HBV, antiviral U1i has been combined with RNAi to demonstrate a strong inhibition of expression from HBV sequences in vivo. This shows that, although several aspects of U1i technology remain to be addressed, U1i and U1i combined with RNAi have great potential as antivirals.

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U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo

Cited by 5 publications

References 58 publications

The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma

The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma

U1 Adaptors Suppress the KRAS-MYC Oncogenic Axis in Human Pancreatic Cancer Xenografts

U1 interference (U1i) for Antiviral Approaches

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