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Ivan D. Horak – One of the best experts on this subject based on the ideXlab platform.

  • Abstract 232: Targeting HER3 mRNA by a locked nucleic Antisense Molecule enhances the antitumor activity of gefitinib in vivo
    Cellular and Molecular Biology, 2011
    Co-Authors: Maoliang Wang, Patricia Kraft, Yixian Zhang, Victoria Shi, Lee M. Greenberger, Ivan D. Horak

    Abstract:

    Background: The HER family consists of four tyrosine kinase receptors designated as EGFR, HER2, HER3 and HER4. HER3 is a unique member that plays a critical role in tumor growth since it 1) can heterodimerize with EGFR or HER2 and is the main link to the downstream PI3K/Akt signaling axis, 2) can mediate resistance to HER1/2-targeted therapeutics, and 3) unlike EGFR or HER2, is not typically overexpressed but still hyperphosphorylated in a variety of tumors. Resistance to the EGFR-tyrosine kinase inhibitors, such as gefitinib, can be associated with EGFR mutations and/or activation of HER3 ultimately leading to activation of the PI3K/AKT axis. We have used an RNA antagonist of HER3, designated EZN-3920, to explore the ability of this compound to inhibit tumor growth and overcome resistance to HER1/2 therapeutics. Methods: Tissue culture cells were treated with EZN-3920, a locked nucleic acid (LNA)-based oligonucleotide complementary to HER3. Compound was either added to tissue culture media (i.e. no transfection) in vitro or prepared in saline and given IV in vivo. Endpoints were measured by qRT-PCR, MTT, Western Blot analysis, Immunohistochemistry, and tumor size. Results: EZN-3920 down modulated HER3 mRNA, protein expression, PI3K/AKT signaling, and inhibited tumor cell proliferation. In vivo, systemic administration of EZN-3920, prepared in saline, resulted in specific down- modulation of HER3 mRNA and protein expression, as well as blockade in PI3K/AKT signaling pathways in NSCLC HCC827 associated with tumor growth inhibition. Similar results were also shown in tumor derived from BT-474-M1 breast carcinoma xenograft models. Interestingly, in the HCC827 tumor model, EZN-3920 at 30 mg/kg (biweekly for 4 weeks, i.v.) and gefitinib at 15 mg/kg (5 times a week for two weeks) completely shrank established tumors while either treatment alone only delayed tumor growth by 40-60%. Conclusions: The studies suggest that down regulation of HER3 by Antisense Molecule EZN-3920 inhibits human tumor growth in mice. Beyond this, antitumor effects of gefitinib can be enhanced by HER3 down modulation in gefitinib-sensitive tumors. On-going studies will determine if tumors that are resistant to HER1/2 therapeutics will either have enhanced sensitivity to EZN-3920 and/or the compound can restore sensitivity to such agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 232. doi:10.1158/1538-7445.AM2011-232

  • Targeting HER3 mRNA by a locked nucleic Antisense Molecule enhances the antitumor activity of gefitinib in vivo
    , 2011
    Co-Authors: Maoliang Wang, Yixian Zhang, Lee M. Greenberger, D. Blanset, Ivan D. Horak

    Abstract:

    Human tumor cells were treated with LNA-ONs without lipofection at the various concentrations. Cell proliferation was examined by MTS assay. The optical densities were measured in a Microplate Reader (Molecular Devices, Sunnyvale, CA, USA) at a wavelength of 490 nm. EZN-3920 was chosen because of its potency and selectivity among tested HER3+ tumor cell lines. Cell proliferation (MTS), mRNA (qRT-PCR), and protein (western blot) examinations were performed 3-5 days after drug incubation.

  • Customized positive PEG linkers for the delivery of Antisense Molecules
    Cancer Research, 2007
    Co-Authors: Hong Zhao, Maoliang Wang, Lee M. Greenberger, Prasanna Reddy, Jing Xia, Syed Ali, Puja Sapra, David Filpula, Chalres Conover, Ivan D. Horak

    Abstract:

    4731 Introduction: Targeting genes has elicit significant effort over last two decades. Initial effort has focused on first generation of oligonucleotide based Molecules as potential therapeutics for various human diseases. Recent progresses in oligonucleotide chemistry helped to introduce second and third generation Antisense technology such as locked nucleic acid (LNA) and silencing RNA (siRNA). Effective systemic delivery of this type of Molecules is still the biggest hurdle to fully realize their therapeutic potential in clinic. Short half-life and poor cellular uptake of highly negative charged feature of oligonucleotides has resulted suboptimal efficacy in xenograft models. To overcome these challenges, here we want to report the development of new Customized positively charged PEG linkers and their application to enhance the cellular uptake of Antisense oligonucleotide, including LNA. Procedure: Customized positively charged PEG linkers were made by incorporating either peptide fragments, or synthetic positive moieties into the backbone of PEG polymer. These PEG polymers were then converted to releasable, tail-free linkers using proprietary technologies before conjugated with Antisense oligonucleotides. The PEG-oligo conjugates were tested for their stability in buffer and plasma. Subsequently, in vitro protein inhibition and target gene down-regulation studies were conducted using Western Blot and Real-Time PCR techniques in a panel of tumor cell lines with and without transfection agents. Summary of Data: The PEG-oligo conjugates are stable under physiological buffer conditions and have shown greatly enhanced stability towards certain nucleases such as phosphodiesterase I (59-exonuclease), phosphodiesterase II (39-exonuclease), and nuclease P1 (endonuclease) in vitro. All the PEG-oligo conjugates have demonstrated a controlled release of native Antisense Molecule in rat plasma. More importantly, PEG-oligo conjugates have shown dose-dependent and specific target gene down-regulation documented by both Western blot and Real-Time PCR studies. Conclusions: PEGylation of oligonucleotide using Customized positively charged PEG linkers has improved the in vitro stability of oligo Molecules and released native Antisense at different rates in plasma. The in vitro activity of PEG-oligo is dose dependent and more efficient than native Molecule, especially in the absence of transfection agents. Safety, efficacy and down-modulation of target gene will be determined using PEG-oligo conjugates in preclinical models. Customized positively charged PEG linkers may provide a unique approach for the more efficient in vivo delivery of Antisense Molecules including LNA to fully realize its therapeutic potential.

Maoliang Wang – One of the best experts on this subject based on the ideXlab platform.

  • Abstract 232: Targeting HER3 mRNA by a locked nucleic Antisense Molecule enhances the antitumor activity of gefitinib in vivo
    Cellular and Molecular Biology, 2011
    Co-Authors: Maoliang Wang, Patricia Kraft, Yixian Zhang, Victoria Shi, Lee M. Greenberger, Ivan D. Horak

    Abstract:

    Background: The HER family consists of four tyrosine kinase receptors designated as EGFR, HER2, HER3 and HER4. HER3 is a unique member that plays a critical role in tumor growth since it 1) can heterodimerize with EGFR or HER2 and is the main link to the downstream PI3K/Akt signaling axis, 2) can mediate resistance to HER1/2-targeted therapeutics, and 3) unlike EGFR or HER2, is not typically overexpressed but still hyperphosphorylated in a variety of tumors. Resistance to the EGFR-tyrosine kinase inhibitors, such as gefitinib, can be associated with EGFR mutations and/or activation of HER3 ultimately leading to activation of the PI3K/AKT axis. We have used an RNA antagonist of HER3, designated EZN-3920, to explore the ability of this compound to inhibit tumor growth and overcome resistance to HER1/2 therapeutics. Methods: Tissue culture cells were treated with EZN-3920, a locked nucleic acid (LNA)-based oligonucleotide complementary to HER3. Compound was either added to tissue culture media (i.e. no transfection) in vitro or prepared in saline and given IV in vivo. Endpoints were measured by qRT-PCR, MTT, Western Blot analysis, Immunohistochemistry, and tumor size. Results: EZN-3920 down modulated HER3 mRNA, protein expression, PI3K/AKT signaling, and inhibited tumor cell proliferation. In vivo, systemic administration of EZN-3920, prepared in saline, resulted in specific down- modulation of HER3 mRNA and protein expression, as well as blockade in PI3K/AKT signaling pathways in NSCLC HCC827 associated with tumor growth inhibition. Similar results were also shown in tumor derived from BT-474-M1 breast carcinoma xenograft models. Interestingly, in the HCC827 tumor model, EZN-3920 at 30 mg/kg (biweekly for 4 weeks, i.v.) and gefitinib at 15 mg/kg (5 times a week for two weeks) completely shrank established tumors while either treatment alone only delayed tumor growth by 40-60%. Conclusions: The studies suggest that down regulation of HER3 by Antisense Molecule EZN-3920 inhibits human tumor growth in mice. Beyond this, antitumor effects of gefitinib can be enhanced by HER3 down modulation in gefitinib-sensitive tumors. On-going studies will determine if tumors that are resistant to HER1/2 therapeutics will either have enhanced sensitivity to EZN-3920 and/or the compound can restore sensitivity to such agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 232. doi:10.1158/1538-7445.AM2011-232

  • Targeting HER3 mRNA by a locked nucleic Antisense Molecule enhances the antitumor activity of gefitinib in vivo
    , 2011
    Co-Authors: Maoliang Wang, Yixian Zhang, Lee M. Greenberger, D. Blanset, Ivan D. Horak

    Abstract:

    Human tumor cells were treated with LNA-ONs without lipofection at the various concentrations. Cell proliferation was examined by MTS assay. The optical densities were measured in a Microplate Reader (Molecular Devices, Sunnyvale, CA, USA) at a wavelength of 490 nm. EZN-3920 was chosen because of its potency and selectivity among tested HER3+ tumor cell lines. Cell proliferation (MTS), mRNA (qRT-PCR), and protein (western blot) examinations were performed 3-5 days after drug incubation.

  • Customized positive PEG linkers for the delivery of Antisense Molecules
    Cancer Research, 2007
    Co-Authors: Hong Zhao, Maoliang Wang, Lee M. Greenberger, Prasanna Reddy, Jing Xia, Syed Ali, Puja Sapra, David Filpula, Chalres Conover, Ivan D. Horak

    Abstract:

    4731 Introduction: Targeting genes has elicit significant effort over last two decades. Initial effort has focused on first generation of oligonucleotide based Molecules as potential therapeutics for various human diseases. Recent progresses in oligonucleotide chemistry helped to introduce second and third generation Antisense technology such as locked nucleic acid (LNA) and silencing RNA (siRNA). Effective systemic delivery of this type of Molecules is still the biggest hurdle to fully realize their therapeutic potential in clinic. Short half-life and poor cellular uptake of highly negative charged feature of oligonucleotides has resulted suboptimal efficacy in xenograft models. To overcome these challenges, here we want to report the development of new Customized positively charged PEG linkers and their application to enhance the cellular uptake of Antisense oligonucleotide, including LNA. Procedure: Customized positively charged PEG linkers were made by incorporating either peptide fragments, or synthetic positive moieties into the backbone of PEG polymer. These PEG polymers were then converted to releasable, tail-free linkers using proprietary technologies before conjugated with Antisense oligonucleotides. The PEG-oligo conjugates were tested for their stability in buffer and plasma. Subsequently, in vitro protein inhibition and target gene down-regulation studies were conducted using Western Blot and Real-Time PCR techniques in a panel of tumor cell lines with and without transfection agents. Summary of Data: The PEG-oligo conjugates are stable under physiological buffer conditions and have shown greatly enhanced stability towards certain nucleases such as phosphodiesterase I (59-exonuclease), phosphodiesterase II (39-exonuclease), and nuclease P1 (endonuclease) in vitro. All the PEG-oligo conjugates have demonstrated a controlled release of native Antisense Molecule in rat plasma. More importantly, PEG-oligo conjugates have shown dose-dependent and specific target gene down-regulation documented by both Western blot and Real-Time PCR studies. Conclusions: PEGylation of oligonucleotide using Customized positively charged PEG linkers has improved the in vitro stability of oligo Molecules and released native Antisense at different rates in plasma. The in vitro activity of PEG-oligo is dose dependent and more efficient than native Molecule, especially in the absence of transfection agents. Safety, efficacy and down-modulation of target gene will be determined using PEG-oligo conjugates in preclinical models. Customized positively charged PEG linkers may provide a unique approach for the more efficient in vivo delivery of Antisense Molecules including LNA to fully realize its therapeutic potential.

Lee M. Greenberger – One of the best experts on this subject based on the ideXlab platform.

  • Abstract 232: Targeting HER3 mRNA by a locked nucleic Antisense Molecule enhances the antitumor activity of gefitinib in vivo
    Cellular and Molecular Biology, 2011
    Co-Authors: Maoliang Wang, Patricia Kraft, Yixian Zhang, Victoria Shi, Lee M. Greenberger, Ivan D. Horak

    Abstract:

    Background: The HER family consists of four tyrosine kinase receptors designated as EGFR, HER2, HER3 and HER4. HER3 is a unique member that plays a critical role in tumor growth since it 1) can heterodimerize with EGFR or HER2 and is the main link to the downstream PI3K/Akt signaling axis, 2) can mediate resistance to HER1/2-targeted therapeutics, and 3) unlike EGFR or HER2, is not typically overexpressed but still hyperphosphorylated in a variety of tumors. Resistance to the EGFR-tyrosine kinase inhibitors, such as gefitinib, can be associated with EGFR mutations and/or activation of HER3 ultimately leading to activation of the PI3K/AKT axis. We have used an RNA antagonist of HER3, designated EZN-3920, to explore the ability of this compound to inhibit tumor growth and overcome resistance to HER1/2 therapeutics. Methods: Tissue culture cells were treated with EZN-3920, a locked nucleic acid (LNA)-based oligonucleotide complementary to HER3. Compound was either added to tissue culture media (i.e. no transfection) in vitro or prepared in saline and given IV in vivo. Endpoints were measured by qRT-PCR, MTT, Western Blot analysis, Immunohistochemistry, and tumor size. Results: EZN-3920 down modulated HER3 mRNA, protein expression, PI3K/AKT signaling, and inhibited tumor cell proliferation. In vivo, systemic administration of EZN-3920, prepared in saline, resulted in specific down- modulation of HER3 mRNA and protein expression, as well as blockade in PI3K/AKT signaling pathways in NSCLC HCC827 associated with tumor growth inhibition. Similar results were also shown in tumor derived from BT-474-M1 breast carcinoma xenograft models. Interestingly, in the HCC827 tumor model, EZN-3920 at 30 mg/kg (biweekly for 4 weeks, i.v.) and gefitinib at 15 mg/kg (5 times a week for two weeks) completely shrank established tumors while either treatment alone only delayed tumor growth by 40-60%. Conclusions: The studies suggest that down regulation of HER3 by Antisense Molecule EZN-3920 inhibits human tumor growth in mice. Beyond this, antitumor effects of gefitinib can be enhanced by HER3 down modulation in gefitinib-sensitive tumors. On-going studies will determine if tumors that are resistant to HER1/2 therapeutics will either have enhanced sensitivity to EZN-3920 and/or the compound can restore sensitivity to such agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 232. doi:10.1158/1538-7445.AM2011-232

  • Targeting HER3 mRNA by a locked nucleic Antisense Molecule enhances the antitumor activity of gefitinib in vivo
    , 2011
    Co-Authors: Maoliang Wang, Yixian Zhang, Lee M. Greenberger, D. Blanset, Ivan D. Horak

    Abstract:

    Human tumor cells were treated with LNA-ONs without lipofection at the various concentrations. Cell proliferation was examined by MTS assay. The optical densities were measured in a Microplate Reader (Molecular Devices, Sunnyvale, CA, USA) at a wavelength of 490 nm. EZN-3920 was chosen because of its potency and selectivity among tested HER3+ tumor cell lines. Cell proliferation (MTS), mRNA (qRT-PCR), and protein (western blot) examinations were performed 3-5 days after drug incubation.

  • Customized positive PEG linkers for the delivery of Antisense Molecules
    Cancer Research, 2007
    Co-Authors: Hong Zhao, Maoliang Wang, Lee M. Greenberger, Prasanna Reddy, Jing Xia, Syed Ali, Puja Sapra, David Filpula, Chalres Conover, Ivan D. Horak

    Abstract:

    4731 Introduction: Targeting genes has elicit significant effort over last two decades. Initial effort has focused on first generation of oligonucleotide based Molecules as potential therapeutics for various human diseases. Recent progresses in oligonucleotide chemistry helped to introduce second and third generation Antisense technology such as locked nucleic acid (LNA) and silencing RNA (siRNA). Effective systemic delivery of this type of Molecules is still the biggest hurdle to fully realize their therapeutic potential in clinic. Short half-life and poor cellular uptake of highly negative charged feature of oligonucleotides has resulted suboptimal efficacy in xenograft models. To overcome these challenges, here we want to report the development of new Customized positively charged PEG linkers and their application to enhance the cellular uptake of Antisense oligonucleotide, including LNA. Procedure: Customized positively charged PEG linkers were made by incorporating either peptide fragments, or synthetic positive moieties into the backbone of PEG polymer. These PEG polymers were then converted to releasable, tail-free linkers using proprietary technologies before conjugated with Antisense oligonucleotides. The PEG-oligo conjugates were tested for their stability in buffer and plasma. Subsequently, in vitro protein inhibition and target gene down-regulation studies were conducted using Western Blot and Real-Time PCR techniques in a panel of tumor cell lines with and without transfection agents. Summary of Data: The PEG-oligo conjugates are stable under physiological buffer conditions and have shown greatly enhanced stability towards certain nucleases such as phosphodiesterase I (59-exonuclease), phosphodiesterase II (39-exonuclease), and nuclease P1 (endonuclease) in vitro. All the PEG-oligo conjugates have demonstrated a controlled release of native Antisense Molecule in rat plasma. More importantly, PEG-oligo conjugates have shown dose-dependent and specific target gene down-regulation documented by both Western blot and Real-Time PCR studies. Conclusions: PEGylation of oligonucleotide using Customized positively charged PEG linkers has improved the in vitro stability of oligo Molecules and released native Antisense at different rates in plasma. The in vitro activity of PEG-oligo is dose dependent and more efficient than native Molecule, especially in the absence of transfection agents. Safety, efficacy and down-modulation of target gene will be determined using PEG-oligo conjugates in preclinical models. Customized positively charged PEG linkers may provide a unique approach for the more efficient in vivo delivery of Antisense Molecules including LNA to fully realize its therapeutic potential.