Down-Modulation of Survivin Expression and Inhibition of Tumor Growth In Vivo by EZN-3042, A Locked Nucleic Acid Antisense Oligonucleotide

Sapra, Puja; Wang, Maoliang; Bandaru, Raj; Zhao, Hong; Greenberger, Lee M.; Horak, Ivan D.

doi:10.1080/15257771003597733

Cited by 38 publications

(38 citation statements)

References 46 publications

(54 reference statements)

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“…EZN-3042, a survivin inhibiting locked nucleic acid antisense oligonucleotide (33,34), and EZN-3046 (scrambled control oligonucleotide) were supplied by Enzon Pharmaceuticals. After demonstration of gene knockdown efficacy in vitro (not shown), mice were injected subcutaneously with 2 Â 10 6 Abrams osteosarcoma cells.…”

Section: Murine Xenograft Experimentsmentioning

confidence: 99%

Expression and Function of Survivin in Canine Osteosarcoma

et al. 2012

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Osteosarcoma has a high mortality rate and remains in need of more effective therapeutic approaches. Survivin is an inhibitor of apoptosis family member protein that blocks apoptosis and drives proliferation in human cancer cells where it is commonly elevated. In this study, we illustrate the superiority of a canine osteosarcoma model as a translational tool for evaluating survivin-directed therapies, owing to the striking similarities in gross and microscopic appearance, biologic behavior, gene expression, and signaling pathway alterations. Elevated survivin expression in primary canine osteosarcoma tissue correlated with increased histologic grade and mitotic index and a decreased disease-free interval (DFI). Survivin attenuation in canine osteosarcoma cells inhibited cell-cycle progression, increased apoptosis, mitotic arrest, and chemosensitivity, and cooperated with chemotherapy to significantly improve in vivo tumor control. Our findings illustrate the utility of a canine system to more accurately model human osteosarcoma and strongly suggest that survivin-directed therapies might be highly effective in its treatment. Cancer Res; 72(1); 249-59. Ó2011 AACR.

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Section: Murine Xenograft Experimentsmentioning

confidence: 99%

Expression and Function of Survivin in Canine Osteosarcoma

et al. 2012

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“…Such LNA oligonucleotides have low single-digit nanomolar or high picomolar IC 50 values for mRNA downmodulation that have been achieved in cell culture for LNA-ASOs against AR as well as HIF-1a (13) and survivin (14,23) when used with transfection reagents. Thus, LNA-ASOs have potencies similar to those of siRNAs but without the inherent instability of siRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…The LNA technology has been used to design antisense molecules to hypoxiainducible factor-1a (HIF-1a; ref. 13) and survivin (14) for the control of cancer as well as a microRNA (miRNA) antagomir that mimics miRNA-122 for the control of cholesterol levels (15) and hepatitis C infection (16). We have designed an LNA-ASO, designated EZN-4176, for ARs and it specifically binds within exon 4 of the AR mRNA and consequently downmodulates AR expression in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Reduced Expression of the Androgen Receptor by Third Generation of Antisense Shows Antitumor Activity in Models of Prostate Cancer

Zhang

Castaneda

Dumble

et al. 2011

Molecular Cancer Therapeutics

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The androgen receptor (AR) is a member of a unique class of transcription factors because it contains a ligand-binding domain that, when activated, results in nuclear translocation and the transcriptional activation of genes associated with prostate cancer development. Although androgen deprivation therapies are effective initially for the treatment of prostate cancer, the disease eventually relapses and progresses to castrationresistant prostate cancer (CRPC). Nonetheless, the AR still plays a critical role because late-stage investigational agents that deplete testosterone (abiraterone) or block ligand binding (MDV3100) can still control tumor growth in patients with CRPC. These findings indicate that downmodulation of AR expression may provide a complementary strategy for treating CRPC. In this article, we describe a novel, locked, nucleic acid-based antisense oligonucleotide, designated EZN-4176. When administered as a single agent, EZN-4176 specifically downmodulated AR mRNA and protein, and this was coordinated with inhibition of the growth of both androgen-sensitive and CRPC tumors in vitro as well as in animal models. The effect was specific because no effect on growth was observed with a control antisense oligonucleotide that does not recognize AR mRNA, nor on tumors derived from the PC3, AR-negative, tumor cell line. In addition, EZN-4176 reduced AR luciferase reporter activity in a CRPC model derived from C4-2b cells that were implanted intratibially, indicating that the molecule may control prostate cancer that has metastasized to the bone. These data, together with the continued dependency of CRPC on the AR signaling pathway, justify the ongoing phase I evaluation of EZN-4176 in patients with CRPC.

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“…[26][27][28] We performed a dose-sensitivity assay with primary pre-B-ALL cells that were treated with increasing concentrations of EZN-3042 (5-20M) as a single agent or with EZN-3088 as control for 7 days. As shown in Figure 4A-G, high amounts of EZN-3042 as a monotreatment after a 7-day treatment were required to affect the viability of primary ALL cells, with varying IC 50 doses.…”

Section: Single-agent Ezn-3042 Is Insufficient To Eradicate Primary Amentioning

confidence: 99%

Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia

Park

Gang

Hsieh

et al. 2011

Blood

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Relapse of drug-resistant acute lymphoblastic leukemia (ALL) has been associated with increased expression of survivin/BIRC5, an inhibitor of apoptosis protein, suggesting a survival advantage for ALL cells. In the present study, we report that inhibition of survivin in patientderived ALL can eradicate leukemia.Targeting survivin with shRNA in combination with chemotherapy resulted in no detectable minimal residual disease in a xenograft model of primary ALL. Similarly, pharmacologic knock-down of survivin using EZN-3042, a novel locked nucleic acid antisense oligonucleotide, in combination with chemotherapy elimi- IntroductionWhereas the overall prognosis for patients with acute lymphoblastic leukemia (ALL) has improved over the past decades, with an overall survival of approximately 45%-60% for adults 1 and approximately 80% for children, 2,3 relapse of drug-resistant leukemia remains a significant problem. Although cure rates in children are high, recurrent leukemia leads to death in 50%-95% of cases depending on the site of recurrence. 4 Moreover, survivors often suffer from secondary neoplasms and chronic or late-occurring health problems. 5 Survivin (BIRC5), a member of the inhibitor of apoptosis protein (IAP) gene family, 6 has been shown to inhibit apoptosis, enhance proliferation and promote angiogenesis, 7,8 but an indirect association with pro-and antiapoptotic proteins has also been described. 7,9,10 Caspase-independent inhibition of cell death has been attributed to the inhibition of apoptosis-inducing factordependent apoptotic pathways, which are known to induce caspaseindependent DNA fragmentation. 11 Death of cells lacking survivin is thought to be due to incomplete mitosis. 12 Survivin is localized to the microtubules of the mitotic spindle, where it plays an essential role in maintaining high fidelity at cell-cycle checkpoints and transitions. 13 Survivin is itself up-regulated in a cell-cycledependent manner at the G 2 /M phase. 14 Survivin associates with Aurora B kinase and Borrealin to form the chromosome passenger complex that is involved in mitosis, 15 cell-cycle progression, and cytokinesis. 16 Survivin was also shown to play a role in the proliferation of leukemia that was induced by internal tandem duplication of FLT3, 17 and may promote tumorigenesis in vivo by imparting a survival advantage. 18 Survivin is selectively expressed in fetal and proliferating tissues and in various solid tumors 19 and hematologic malignancies. 20 In addition, elevated survivin expression in cancer has been associated with poor prognosis. In particular, gene-expression analysis of matched diagnosis-relapse pairs of ALL samples revealed higher expression levels of survivin at relapse than at diagnosis. 21 However, whether survivin inhibition can actually prevent relapse in primary ALL has not been examined. In the present study, we investigated the role of survivin in primary ALL and evaluated survivin as a potential target for therapy of primary ALL. Methods Patient samplesBone marrow and peripheral blood...

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Down-Modulation of Survivin Expression and Inhibition of Tumor Growth In Vivo by EZN-3042, A Locked Nucleic Acid Antisense Oligonucleotide

Cited by 38 publications

References 46 publications

Expression and Function of Survivin in Canine Osteosarcoma

Expression and Function of Survivin in Canine Osteosarcoma

Reduced Expression of the Androgen Receptor by Third Generation of Antisense Shows Antitumor Activity in Models of Prostate Cancer

Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia

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