A Phase I Study of OGX-011, a 2′-Methoxyethyl Phosphorothioate Antisense to Clusterin, in Combination with Docetaxel in Patients with Advanced Cancer

N., Kim; Siu, Lillian L.; Hirte, H.; Hotte, Sébastien J.; Knox, J. David; Kollmansberger, Christian K.; Gleave, Martin; Guns, Emma S. Tomlinson; Powers, Jean; Walsh, William R.; Tu, Dongsheng; Eisenhauer, Elizabeth

doi:10.1158/1078-0432.ccr-07-1310

Cited by 112 publications

(56 citation statements)

References 21 publications

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“…Consistent with these accumulated findings (43), inhibition of CLU with OGX-011 synergistically enhances conventional and molecular targeted therapies in prostate cancer preclinical models (25). Indeed, OGX-011 is now in phase III trials, as phase II studies reported more than 90% inhibition of CLU in human prostate cancer tissues (44) and 7 months prolonged survival when OGX-011 is combined with docetaxel in CRPC (45,46).…”

Section: Discussionmentioning

confidence: 77%

Clusterin Inhibition Using OGX-011 Synergistically Enhances Hsp90 Inhibitor Activity by Suppressing the Heat Shock Response in Castrate-Resistant Prostate Cancer

et al. 2011

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Small-molecule inhibitors of Hsp90 show promise in the treatment of castrate-resistant prostate cancer (CRPC); however, these inhibitors trigger a heat shock response that attenuates drug effectiveness. Attenuation is associated with increased expression of Hsp90, Hsp70, Hsp27, and clusterin (CLU) that mediate tumor cell survival and treatment resistance. We hypothesized that preventing CLU induction in this response would enhance Hsp90 inhibitor-induced CRPC cell death in vitro and in vivo. To test this hypothesis, we treated CRPC with the Hsp90 inhibitor PF-04929113 or 17-AAG in the absence or presence of OGX-011, an antisense drug that targets CLU. Treatment with either Hsp90 inhibitor alone increased nuclear translocation and transcriptional activity of the heat shock factor HSF-1, which stimulated dose-and time-dependent increases in HSP expression, especially CLU expression. Treatment-induced increases in CLU were blocked by OGX-011, which synergistically enhanced the activity of Hsp90 inhibition on CRPC cell growth and apoptosis. Accompanying these effects was a decrease in HSF-1 transcriptional activity as well as expression of HSPs, Akt, prostate-specific antigen, and androgen receptor. In vivo evaluation of the Hsp90 inhibitors with OGX-011 in xenograft models of human CRPC showed that OGX-011 markedly potentiated antitumor efficacy, leading to an 80% inhibition of tumor growth with prolonged survival compared with Hsp90 inhibitor monotherapy. Together, our findings indicate that Hsp90 inhibitor-induced activation of the heat shock response and CLU is attenuated by OGX-011, with synergistic effects on delaying CRPC progression. Cancer Res; 71(17); 5838-49. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 77%

Clusterin Inhibition Using OGX-011 Synergistically Enhances Hsp90 Inhibitor Activity by Suppressing the Heat Shock Response in Castrate-Resistant Prostate Cancer

et al. 2011

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“…MicroRNA-based cancer gene therapy (reviewed by Tong andNemunaitis, 2008 andWeinberg, 2009a) offers the possibility of targeting multiple gene networks controlled by an individual miRNA (Valastyan and Weinberg, 2009b). The efficacy of localized small interfering RNA-based therapeutics (Devi, 2006;de Fougerolles et al, 2007;Davis et al, 2010) against various tumors is currently being assessed in a number of ongoing clinical trials (Tolcher et al, 2002;Chi et al, 2008;Hau et al, 2009). Similarly, miRNAs can be inhibited in vitro with specific cholesterol conjugated (Krutzfeldt et al, 2005), 2 0 -Omethyl oligonucleotide antagonists (AMOs) or 'antagomirs', when delivered as liposomal complexes, or nonconjugated (Esau et al, 2006) into mice, rats and nonhuman primates (Elmen et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Efficient in vivo microRNA targeting of liver metastasis

et al. 2010

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Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2 0 sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNAcontrolled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors.

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“…Among the stress signals that cause up-regulation of clusterin are chemotherapy, irradiation, and hormone ablation (28, 30, 31, 46 -49). A clusterin-inhibiting antisense oligonucleotide has been reported as a potential treatment for increasing the susceptibility of solid tumors to conventional cancer therapies (50,51). Here, we demonstrate that clusterin-I, designed as an antagonist of clusterin, has anticancer effect in vitro (Fig.…”

Section: Discussionmentioning

confidence: 53%

Peptides modulating conformational changes in secreted chaperones: From in silico design to preclinical proof of concept

Kliger

Levy

Oren

et al. 2009

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

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Blocking conformational changes in biologically active proteins holds therapeutic promise. Inspired by the susceptibility of viral entry to inhibition by synthetic peptides that block the formation of helixhelix interactions in viral envelope proteins, we developed a computational approach for predicting interacting helices. Using this approach, which combines correlated mutations analysis and Fourier transform, we designed peptides that target gp96 and clusterin, 2 secreted chaperones known to shift between inactive and active conformations. In human blood mononuclear cells, the gp96-derived peptide inhibited the production of TNF␣, IL-1␤, IL-6, and IL-8 induced by endotoxin by >80%. When injected into mice, the peptide reduced circulating levels of endotoxin-induced TNF␣, IL-6, and IFN␥ by >50%. The clusterin-derived peptide arrested proliferation of several neoplastic cell lines, and significantly enhanced the cytostatic activity of taxol in vitro and in a xenograft model of lung cancer. Also, the predicted mode of action of the active peptides was experimentally verified. Both peptides bound to their parent proteins, and their biological activity was abolished in the presence of the peptides corresponding to the counterpart helices. These data demonstrate a previously uncharacterized method for rational design of protein antagonists.cancer ͉ contact map prediction ͉ cytokines ͉ inflammation ͉ helix C onformational changes in proteins have an essential role in regulating activity. Natural and synthetic molecules that modulate such changes are of considerable biological importance. Such molecules include allosteric effectors that alter the rate of enzymecatalyzed reactions (1), molecules that shift the oligomerization equilibrium of proteins (2), and molecules that interfere with transmembrane helix-helix associations (3).Conformational changes that have been extensively studied are those that take place during viral-induced membrane fusion. This process is required for the propagation of enveloped viruses, and is facilitated by viral encoded type 1 integral membrane proteins (4, 5). Viral entry of enveloped viruses depends on a conformational change involving the formation of helix-helix interactions, i.e., 2 alpha helices that do not interact in the native (nonfusogenic) state, but do interact with each other when the protein folds into its fusion-active (fusogenic) form. Remarkably, synthetic peptides corresponding to some of these helical segments have an antiviral activity (6 -8), of which one has been developed for the treatment of HIV-1 infection (9, 10).We hypothesized that such a mode of inhibition could be also applied on nonviral proteins. The aim of the present study was to develop a computational tool for the detection of intramolecular helix-helix interactions and to use this tool for detecting such interacting helices in proteins of interest. This study focuses on secreted chaperones due to their biological and therapeutic relevance (11-14), and because conformational changes are known to take p...

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A Phase I Study of OGX-011, a 2′-Methoxyethyl Phosphorothioate Antisense to Clusterin, in Combination with Docetaxel in Patients with Advanced Cancer

Cited by 112 publications

References 21 publications

Clusterin Inhibition Using OGX-011 Synergistically Enhances Hsp90 Inhibitor Activity by Suppressing the Heat Shock Response in Castrate-Resistant Prostate Cancer

Clusterin Inhibition Using OGX-011 Synergistically Enhances Hsp90 Inhibitor Activity by Suppressing the Heat Shock Response in Castrate-Resistant Prostate Cancer

Efficient in vivo microRNA targeting of liver metastasis

Peptides modulating conformational changes in secreted chaperones: From in silico design to preclinical proof of concept

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