GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Association for Cancer Research (AACR)  (4)
  • Abrams, Marc T.  (4)
  • English  (4)
Material
Publisher
  • American Association for Cancer Research (AACR)  (4)
Person/Organisation
Language
  • English  (4)
Years
Subjects(RVK)
  • 1
    Online Resource
    Online Resource
    Abstract 3536: Targeting β-catenin with a Dicer-substrate siRNA (DsiRNA) in a sleeping beauty transposon-driven murine hepatoblastoma model
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3536-3536
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3536-3536
    Abstract: Hepatoblastoma (HB), the commonest pediatric liver tumor is frequently associated with an N-terminal deletion in the CTNNB1 gene, which encodes stable β-catenin and promotes nuclear localization and transactivation activity. In 80% of patients, nuclear localization of β-catenin and Yes Associated Protein (YAP), a Hippo-related transactivator, is seen together. Further, stable hepatic co-expression of Δ90-CTNNB1 and active-YAP in mice causes rapid and aggressive HB. Dicer-substrate siRNAs (DsiRNAs) are potent RNA interference (RNAi) triggers that that are efficacious in preclinical tumor models of diverse origin, and are currently under clinical evaluation. To determine if CTNNB1-targeting DsiRNAs have potential as a therapy in HB, we encapsulated this oligonucleotide payload into lipid nanoparticles (LNPs), and systemically administered into mice bearing CTNNB1/YAP-induced HB. The LNP platform used, termed EnCore (because of its specific Envelope and Core lipid components), enables high encapsulation efficiency, long-term stability, and consistent analytical criteria. Downstream of LNP-mediated DsiRNA delivery, both qPCR and in situ hybridization were used to visualize changes in CTNNB1 expression in both tumor and normal liver. Robust and specific silencing of CTNNB1 mRNA was achieved in the tumors. The distribution of mRNA knockdown within each tumor nodule suggests efficient extravasation and internalization of the LNP and its payload into the tumor parenchyma, in contrast to previous reports of vascular-channel limited nanoparticle accumulation in tumors. Intriguingly, a “liver-centric” LNP formulation, which delivers cargo efficiently to a normal liver due to rapid hepatic extraction and apolipoprotein-mediated internalization, was inactive in the tumors. Further evaluation demonstrated efficacy of β-catenin targeting in this model. In conclusion, we report a highly relevant modality of RNAi delivery in a mouse model of hepatoblastoma to target a classically-undruggable oncogene. Citation Format: Marc T. Abrams, Junyan Tao, Shanthi Ganesh, Wendy Cyr, Bo Ying, Martin Koser, Rokhand Arvan, Girish Chopda, Hank Dudek, Cheng Lai, Weimin Wang, Bob Brown, Satdarshan Monga. Targeting β-catenin with a Dicer-substrate siRNA (DsiRNA) in a sleeping beauty transposon-driven murine hepatoblastoma model. [abstract] . In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3536. doi:10.1158/1538-7445.AM2015-3536
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-3536
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin
    American Association for Cancer Research (AACR) ; 2016
    In:  Molecular Cancer Therapeutics Vol. 15, No. 9 ( 2016-09-01), p. 2143-2154
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 9 ( 2016-09-01), p. 2143-2154
    Abstract: The Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level and therefore can be applied to previously undruggable targets. Lipid nanoparticles (LNP) represent an elegant solution for the delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have been mostly restricted to applications in the liver. In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Significant tumor growth inhibition was achieved in Wnt-dependent colorectal and hepatocellular carcinoma models, but not in Wnt-independent tumors. Finally, no evidence of accelerated blood clearance or sustained liver transaminase elevation was observed after repeated dosing in nonhuman primates. These data support further investigation to gain mechanistic insight, optimize dose regimens, and identify efficacious combinations with standard-of-care therapeutics. Mol Cancer Ther; 15(9); 2143–54. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-16-0309
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract 3533: Systemic delivery of CTNNB1 Dicer-substrate siRNAs (DsiRNAs) leads to efficient oncogene silencing in diverse tumor types of extra hepatic origin
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3533-3533
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3533-3533
    Abstract: The β-catenin/Wnt pathway is consistently activated in human tumors, including & gt;50% of hepatocellular carcinomas (HCC) and & gt;80% of colorectal cancers (CRC). This is often caused directly by tumorigenic mutations in the CTNNB1 gene, which encodes β-catenin protein. Preclinical evidence in genetic cancer models strongly suggests that inhibiting β-catenin function would yield therapeutic benefit to many cancer patients. Since β-catenin is very challenging to target via conventional modalities, no efficacious therapy targeting β-catenin has emerged despite decades of research. RNA interference (RNAi) technology has enabled the inhibition of previously undruggable targets at the mRNA level and has advanced to late-stage clinical development for several indications. However, the clinical application of RNAi has proven to be most successful for targeting mRNAs in the normal liver, and challenges remain with developing formulations that efficiently deliver to extra-hepatic tumors. Here we describe the development and characterization of a platform to treat tumors of diverse primary tissue origin and metastatic location with CTNNB1-targeting DsiRNA. Tumor types tested included xenograft tumors of colorectal origin (CRC), experimental melanoma lung metastases, and difficult-to-transfect leukemia cells which have infiltrated the spleen. In addition to strong silencing of CTNNB1 mRNA, & gt;75% inhibition of tumor growth was observed for a CRC xenograft model. This was achieved by formulating the DisRNA payload in a lipid nanoparticle (LNP) platform termed EnCore (because of its specific Envelope and Core lipid components). EnCore activity against multiple tumors was further improved by optimizing critical cationic lipid and PEG-lipid components. Importantly, studies in knockout mice demonstrate that in vivo tumor activity is independent of Apolipoprotein E, which has been widely described as an essential endogenous ligand for internalization of LNPs into hepatocytes. This strongly suggests that Encore-mediated delivery to tumors in vivo is independent of the ApoE/LDLR system. DCR-MYC, an EnCore-delivered DsiRNA targeting MYC mRNA, is currently in Phase I clinical trials. Further evaluation of LNP-delivered DsiRNAs in PK/PD and efficacy models, including PDX and GEMM will guide a clinical development strategy for CTNNB1 DsiRNA. Citation Format: Shanthi Ganesh, Bo Ying, Martin Koser, Wendy Cyr, Girish Chopda, Hank Dudek, Cheng Lai, Weimin Wang, Bob Brown, Marc T. Abrams. Systemic delivery of CTNNB1 Dicer-substrate siRNAs (DsiRNAs) leads to efficient oncogene silencing in diverse tumor types of extra hepatic origin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3533. doi:10.1158/1538-7445.AM2015-3533
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-3533
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 2 ( 2018-02-01), p. 544-553
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 2 ( 2018-02-01), p. 544-553
    Abstract: Colorectal carcinomas harbor well-defined genetic abnormalities, including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. Although the MAPK pathway can be targeted using potent small-molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNAi approaches have advanced to the stage of clinical viability and are especially well suited for transcriptional modulators, such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacologic agents. Using a recently described tumor-selective nanoparticle containing a β-catenin–targeting RNAi trigger, in combination with the FDA-approved MEK inhibitor (MEKi) trametinib, we demonstrate synergistic tumor growth inhibition in in vivo models of colorectal cancer, melanoma, and hepatocellular carcinoma. At dose levels that were insufficient to significantly impact tumor growth as monotherapies, combination regimens resulted in synergistic efficacy and complete tumor growth inhibition. Importantly, dual MEKi/RNAi therapy dramatically improved survival of mice bearing colorectal cancer liver metastases. In addition, pharmacologic silencing of β-catenin mRNA was effective against tumors that are inherently resistant or that acquire drug-induced resistance to trametinib. These results provide a strong rationale for clinical evaluation of this dual-targeting approach for cancers harboring Wnt/β-catenin and MAPK pathway mutations. Mol Cancer Ther; 17(2); 544–53. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-17-0605
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...