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  • 1
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    Online Resource
    Ibrutinib Potentiates Antihepatocarcinogenic Efficacy of Sorafenib by Targeting EGFR in Tumor Cells and BTK in Immune Cells in the Stroma
    American Association for Cancer Research (AACR) ; 2020
    In:  Molecular Cancer Therapeutics Vol. 19, No. 2 ( 2020-02-01), p. 384-396
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 19, No. 2 ( 2020-02-01), p. 384-396
    Abstract: Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, is a leading cause of cancer-related death worldwide because of rising incidence and limited therapy. Although treatment with sorafenib or lenvatinib is the standard of care in patients with advanced-stage HCC, the survival benefit from sorafenib is limited due to low response rate and drug resistance. Ibrutinib, an irreversible tyrosine kinase inhibitor (TKI) of the TEC (e.g., BTK) and ErbB (e.g., EGFR) families, is an approved treatment for B-cell malignancies. Here, we demonstrate that ibrutinib inhibits proliferation, spheroid formation, and clonogenic survival of HCC cells, including sorafenib-resistant cells. Mechanistically, ibrutinib inactivated EGFR and its downstream Akt and ERK signaling in HCC cells, and downregulated a set of critical genes involved in cell proliferation, migration, survival, and stemness, and upregulated genes promoting differentiation. Moreover, ibrutinib showed synergy with sorafenib or regorafenib, a sorafenib congener, by inducing apoptosis of HCC cells. In vivo, this TKI combination significantly inhibited HCC growth and prolonged survival of immune-deficient mice bearing human HCCLM3 xenograft tumors and immune-competent mice bearing orthotopic mouse Hepa tumors at a dose that did not exhibit systemic toxicity. In immune-competent mice, the ibrutinib–sorafenib combination reduced the numbers of BTK+ immune cells in the tumor microenvironment. Importantly, we found that the BTK+ immune cells were also enriched in the tumor microenvironment in a subset of primary human HCCs. Collectively, our findings implicate BTK signaling in hepatocarcinogenesis and support clinical trials of the sorafenib–ibrutinib combination for this deadly disease.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-19-0135
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    SSG: 12
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  • 2
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    Online Resource
    Abstract 3470: Ibrutinib and sorafenib synergistically inhibit HCC growth in preclinical models
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3470-3470
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3470-3470
    Abstract: Hepatocellular carcinoma (HCC) is the second major cause of cancer-related death worldwide with limit therapeutic options. Thus, there is an urgent need to develop novel alternative therapies for HCC. In this study, we report that ibrutinib, recently approved for the treatment of B cell malignancies, and a covalent inhibitor of TEC (BTK, ITK etc.) and ERBB (EGFR, Her2 etc.) family of tyrosine kinases, inhibits tumorigenic functions of human HCC cells in vitro and in xenografts. More importantly, co-treatment with ibrutinib and sorafenib, an approved targeted therapy for advanced HCCs that marginally improve patients' survival, synergistically inhibited proliferation and clonogenic survival of HCC cells including those with acquired sorafenib resistance. Mechanistically, ibrutinib inhibits Akt and ERK signaling pathways through inactivating EGFR, its irreversible substrate in HCC cells. Besides, tumor sphere formation and expression of cancer stem cell markers were suppressed by ibrutinib and sorafenib co-treatment in HCC cells. Ectopic expression of the constitutively active Akt mutant abrogated the synergism of these two kinase inhibitors on HCC cell survival. Ibrutinib and sorafenib combination therapy significantly suppressed tumor growth of highly aggressive HCCLM3 subcutaneous xenografts in NSG mice. Collectively, these results demonstrate that ibrutinib could be a re-purposed anti-HCC drug, and our data provides the evidence for the therapeutic potential of ibrutinib and sorafenib combination as an effective and attractive strategy for treating HCCs including those with sorafenib resistance. Citation Format: Kalpana Ghoshal, Cho-hao Lin, Khadija Elkholy, Nissar A. Wani, Ding Li, Juan M. Barajas, Peng Hu, Xiaoli Zhang, Lianbo Yu, Tasneem Motiwala. Ibrutinib and sorafenib synergistically inhibit HCC growth in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3470.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3470
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
    Online Resource
    Online Resource
    Structure-Based Design of Hepatitis C Virus E2 Glycoprotein Improves Serum Binding and Cross-Neutralization
    American Society for Microbiology ; 2020
    In:  Journal of Virology Vol. 94, No. 22 ( 2020-10-27)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 94, No. 22 ( 2020-10-27)
    Abstract: An effective vaccine for hepatitis C virus (HCV) is a major unmet need, and it requires an antigen that elicits immune responses to key conserved epitopes. Based on structures of antibodies targeting HCV envelope glycoprotein E2, we designed immunogens to modulate the structure and dynamics of E2 and favor induction of broadly neutralizing antibodies (bNAbs) in the context of a vaccine. These designs include a point mutation in a key conserved antigenic site to stabilize its conformation, as well as redesigns of an immunogenic region to add a new N-glycosylation site and mask it from antibody binding. Designs were experimentally characterized for binding to a panel of human monoclonal antibodies (HMAbs) and the coreceptor CD81 to confirm preservation of epitope structure and preferred antigenicity profile. Selected E2 designs were tested for immunogenicity in mice, with and without hypervariable region 1, which is an immunogenic region associated with viral escape. One of these designs showed improvement in polyclonal immune serum binding to HCV pseudoparticles and neutralization of isolates associated with antibody resistance. These results indicate that antigen optimization through structure-based design of the envelope glycoproteins is a promising route to an effective vaccine for HCV. IMPORTANCE Hepatitis C virus infects approximately 1% of the world’s population, and no vaccine is currently available. Due to the high variability of HCV and its ability to actively escape the immune response, a goal of HCV vaccine design is to induce neutralizing antibodies that target conserved epitopes. Here, we performed structure-based design of several epitopes of the HCV E2 envelope glycoprotein to engineer its antigenic properties. Designs were tested in vitro and in vivo , demonstrating alteration of the E2 antigenic profile in several cases, and one design led to improvement of cross-neutralization of heterologous viruses. This represents a proof of concept that rational engineering of HCV envelope glycoproteins can be used to modulate E2 antigenicity and optimize a vaccine for this challenging viral target.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.00704-20
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
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  • 4
    Online Resource
    Online Resource
    Design of a native-like secreted form of the hepatitis C virus E1E2 heterodimer
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 3 ( 2021-01-19)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 3 ( 2021-01-19)
    Abstract: Hepatitis C virus (HCV) is a major worldwide health burden, and a preventive vaccine is needed for global control or eradication of this virus. A substantial hurdle to an effective HCV vaccine is the high variability of the virus, leading to immune escape. The E1E2 glycoprotein complex contains conserved epitopes and elicits neutralizing antibody responses, making it a primary target for HCV vaccine development. However, the E1E2 transmembrane domains that are critical for native assembly make it challenging to produce this complex in a homogenous soluble form that is reflective of its state on the viral envelope. To enable rational design of an E1E2 vaccine, as well as structural characterization efforts, we have designed a soluble, secreted form of E1E2 (sE1E2). As with soluble glycoprotein designs for other viruses, it incorporates a scaffold to enforce assembly in the absence of the transmembrane domains, along with a furin cleavage site to permit native-like heterodimerization. This sE1E2 was found to assemble into a form closer to its expected size than full-length E1E2. Preservation of native structural elements was confirmed by high-affinity binding to a panel of conformationally specific monoclonal antibodies, including two neutralizing antibodies specific to native E1E2 and to its primary receptor, CD81. Finally, sE1E2 was found to elicit robust neutralizing antibodies in vivo. This designed sE1E2 can both provide insights into the determinants of native E1E2 assembly and serve as a platform for production of E1E2 for future structural and vaccine studies, enabling rational optimization of an E1E2-based antigen.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2015149118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
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    SSG: 11
    SSG: 12
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