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  • American Association for Cancer Research (AACR)  (14)
  • 1
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    Online Resource
    Development of a Function-Blocking Antibody Against Fibulin-3 as a Targeted Reagent for Glioblastoma
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 4 ( 2018-02-15), p. 821-833
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 4 ( 2018-02-15), p. 821-833
    Abstract: Purpose: We sought a novel approach against glioblastomas (GBM) focused on targeting signaling molecules localized in the tumor extracellular matrix (ECM). We investigated fibulin-3, a glycoprotein that forms the ECM scaffold of GBMs and promotes tumor progression by driving Notch and NFκB signaling. Experimental Design: We used deletion constructs to identify a key signaling motif of fibulin-3. An mAb (mAb428.2) was generated against this epitope and extensively validated for specific detection of human fibulin-3. mAb428.2 was tested in cultures to measure its inhibitory effect on fibulin-3 signaling. Nude mice carrying subcutaneous and intracranial GBM xenografts were treated with the maximum achievable dose of mAb428.2 to measure target engagement and antitumor efficacy. Results: We identified a critical 23-amino acid sequence of fibulin-3 that activates its signaling mechanisms. mAb428.2 binds to that epitope with nanomolar affinity and blocks the ability of fibulin-3 to activate ADAM17, Notch, and NFκB signaling in GBM cells. mAb428.2 treatment of subcutaneous GBM xenografts inhibited fibulin-3, increased tumor cell apoptosis, and enhanced the infiltration of inflammatory macrophages. The antibody reduced tumor growth and extended survival of mice carrying GBMs as well as other fibulin-3–expressing tumors. Locally infused mAb428.2 showed efficacy against intracranial GBMs, increasing tumor apoptosis and reducing tumor invasion and vascularization, which are enhanced by fibulin-3. Conclusions: To our knowledge, this is the first rationally developed, function-blocking antibody against an ECM target in GBM. Our results offer a proof of principle for using “anti-ECM” strategies toward more efficient targeted therapies for malignant glioma. Clin Cancer Res; 24(4); 821–33. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-1628
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
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    Abstract 3954: Validation of the extracellular matrix protein fibulin-3 as a molecular target in malignant pleural mesothelioma
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3954-3954
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3954-3954
    Abstract: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor of the pleura with poor prognosis and limited therapeutic options. Fibulin-3 (gene EFEMP1) is an extracellular matrix protein found in the parenchyma and pleural effusions of MPM, which has been proposed as prognostic biomarker complementing diagnostic biomarkers -such as mesothelin- for this cancer type. However, the functions and potential mechanisms of fibulin-3 in MPM remain completely unknown. To further define the relevance of fibulin-3 in MPM we performed gain- and loss-of-function experiments by respectively overexpressing fibulin-3 in normal mesothelial cells or knocking down its expression in MPM cells, followed by evaluation of cell viability, colony formation, invasion and chemoresistance. We also evaluated changes in gene expression and signaling mechanisms after fibulin-3 downregulation. Furthermore, a novel anti-fibulin-3 antibody was developed and tested for its ability to recognize fibulin-3 in mesothelioma, inhibit pro-tumoral signaling, and disrupt tumor growth in orthotopic MPM models. Fibulin-3 downregulation decreased viability, clonogenic capacity, and invasiveness of MPM cell lines, whereas overexpression of this protein increased the same phenotypic traits in normal mesothelial cells. At the molecular level, fibulin-3 regulated the activation of PI3K/Akt and NFkB signaling and correlated with a gene expression signature required for cell adhesion and motility, matching its cellular effects. Loco-regional delivery of anti-fibulin-3 had a marked cytostatic effect and significantly increased median survival and the number of long-term surviving animals with stable disease. Our work reveals that fibulin-3 is a relevant therapeutic target in mesothelioma, adding to its relevance as prognostic biomarker and encouraging further development of anti-fibulin-3 targeted therapies for this cancer type. Citation Format: Arivazhagan Roshini, Chandra Goparaju, Mohan S. Nandhu, Sharon L. Longo, John A. Longo, Joan Chou, Frank A. Middleton, Harvey I. Pass, Mariano S. Viapiano. Validation of the extracellular matrix protein fibulin-3 as a molecular target in malignant pleural mesothelioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3954.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3954
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    Abstract 3167: The scaffolding protein DLG5 is necessary to maintain Sonic Hedgehog signaling in glioblastoma stem cells and promote tumor growth
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3167-3167
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3167-3167
    Abstract: Proteins complexes that maintain the apico-basal polarity of epithelial cells and organize cell-signaling domains are necessary for normal tissue organization and therefore regarded as tumor suppressors. Accordingly, the scaffolding proteins that form the Scribble polarity complex (SCRIB, LLGL1, and DLG members) are usually downregulated in cancer, in particular in highly aggressive or invasive tumors. Because gliomas arise from non-epithelial precursors that are likely motile before transformation, the expression and functions of these scaffolding proteins in malignant brain tumors has remained almost entirely unexplored. Surprisingly, we have found that one member of the DLG family, DLG5, is highly upregulated in malignant gliomas compared to other solid tumors. Indeed, DLG5 was the predominant DLG member found in all molecular subtypes of glioblastoma (GBM). Knockdown of DLG5 reduced the viability, invasiveness, and self-renewal of GBM stem cells belonging to the proneural and mesenchymal molecular subtypes. As a result, intracranial tumors defficient in DLG5 were smaller and less proliferative than controls, resulting in extended animal survival. At the molecular level, DLG5 knockdown decreased the expression of stemness-related genes (SOX2, NANOG, POU5F1) but increased the expression of LLGL1, a component of the Scribble complex that is associated with neural precursor differentiation. These changes were accompanied by downregulation of Sonic Hedgehog (SHh) signaling, both in vitro and in vivo, which drives GBM cell stemness and proliferation. Moreover, DLG5-deficient GBM stem cells became insensitive to exogenous SHh and were unable to upregulate Gli1 or increase cell invasion in presence of added SHh, compared to control cells. We further confirmed that DLG5 downregulation increased the ubiquitination of Gli1-containing complexes as well as Gli1 proteasomal degradation, providing a suitable mechanism for the loss of SHh signaling and tumor stemness. These results describe for the first time the expression of a DLG family member in malignant gliomas and reveal a novel, polarity-independent, pro-tumoral function of DLG5, which differs from its proposed tumor-suppressor role in other solid tumors. Citation Format: Somanath Kundu, Mohan S. Nandhu, Sharon L. Longo, John A. Longo, Shawn Rai, Lawrence S. Chin, Timothy E. Richardson, Mariano S. Viapiano. The scaffolding protein DLG5 is necessary to maintain Sonic Hedgehog signaling in glioblastoma stem cells and promote tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3167.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-3167
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
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    Abstract 2045: Analysis of the matrisome in malignant gliomas reveals architectural heterogeneity of the tumor microenvironment and discloses a prognostic signature of extracellular matrix targets
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2045-2045
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2045-2045
    Abstract: Novel strategies against malignant gliomas are devoting increasing effort to disrupting the tumor microenvironment (TME), hoping to overcome the challenges posed by the genetic heterogeneity of the tumor cells. The tumor extracellular matrix (ECM) organizes the cytoarchitecture of the TME and presents highly accessible potential targets; strikingly, a systematic analysis of glioma ECM is still missing. To address this gap we performed bioinformatic analysis of the entire matrisome complement of glioblastoma (GBM) and low-grade gliomas (LGG), adding a set of surrogate genes to assess non-protein ECM components predominant in the brain, such as hyaluronic acid. We utilized RNAseq data from the GBM/LGG TCGA dataset (N=668 tumors) as well as our own collection of bulk-sequenced GBM (N=90) and GBM stem cells (N=45). We also supplemented TCGA normal brain data with high-depth sequencing from the subependymal zone of normal adult individuals (N=28), thus assessing the ECM of the putative niche of origin of GBM. Unsupervised K-medoid clustering revealed four GBM clusters defined by ECM differences, two of which superimposed well with classical and proneural classification of GBM. The other two clusters shared features of mesenchymal GBMs but were well differentiated by expression of fibrillar versus non-fibrillar collagens and MMP versus ADAM proteases, suggesting different phenotypes for ECM architecture and remodeling. Extension of this analysis to LGGs identified six well-defined, matrisome-dependent tumor clusters that were independent of histology, transcriptional subtypes, or IDH1 status. Age-adjusted multivariate Cox analysis revealed one particular GBM cluster with "neurodevelopmental-like" ECM having significantly extended overall survival. Using stringent filtering criteria to select ECM genes expressed in GBM we identified 93 candidate ECM genes consistently upregulated across all matrisome or transcriptional subtypes. Regional analysis of these genes allocated most of them to the microvascularized regions of the tumor, suggesting that the most significant ECM remodeling is associated with vascularization rather than tumor invasion. Ongoing scRNAseq analysis suggests that ECM remodeling genes are largely expressed by the tumor cells and tumor-associated astrocytes, with little contribution of myeloid cells, departing from what has been observed in other solid tumors. In sum, these results provide for the first time a comprehensive description of the heterogeneity of the glioma ECM and reveal both a prognostic signature and a number of attractive actionable targets exposed in the TME of these brain cancers. Citation Format: Minhein Htet, Somanath Kundu, Abigail Venskus, Cynthia S. Weickert, Yasir Ahmed-Braimah, Mariano S. Viapiano. Analysis of the matrisome in malignant gliomas reveals architectural heterogeneity of the tumor microenvironment and discloses a prognostic signature of extracellular matrix targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Par t 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2045.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-2045
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Abstract 3148: A novel mechanism of glioblastoma cell invasion regulated by a neural proteoglycan that activates Src/EGFR signaling and mediates tumor-astroglia cooperation
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 3148-3148
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 3148-3148
    Abstract: The goal of this study was to investigate a novel mechanism by which neural extracellular matrix (ECM) proteins regulate the invasive behavior of malignant gliomas, which are the most common primary brain tumors in adults. Invasion of glioma cells is facilitated by secreted metalloproteases that cleave ECM proteoglycans that inhibit cell migration. Surprisingly, glioma cells also produce these proteoglycans at higher levels than normal neural cells, which appears paradoxical. One of these proteoglycans, brevican (BCAN), is uniquely expressed in the CNS, is the most abundant chondroitin-sulfate proteoglycan in the adult brain ECM, and is upregulated in all low-grade gliomas and glioblastomas independently of their molecular subtype. The functions of brevican, both in normal neural cells or glioma cells, remain unknown and are assumed to be purely structural. We analyzed the signaling mechanisms of brevican using gain- and loss-of-function approaches in differentiated glioblastoma cell lines as well as tumor stem cells, combined with experiments of cell adhesion and invasion in vitro and in vivo. We discovered that a fragment of brevican, but not the full-length protein, interacts with cell-surface sulfatides and activates Src kinase, resulting in trans-activation of EGFR/MAPK signaling even in absence of the native EGFR ligands (TGF-alpha or EGF). Brevican-enhanced EGFR/MAPK activation resulted in increased cell adhesion -via fibronectin production- and motility, which were reversed using Src inhibitors or by treating the cells with aryl-sulfatase that removes sulfatides from the cell surface. Importantly, we observed that brevican secreted by glioblastoma cells was cleaved not only by these cells but also by normal astrocytes that were co-opted by the tumor cells. Absence of this cooperative effect was observed when tumors were implanted in an EGFR-deficient mouse model in which astrocytes did not process glioma-derived brevican, resulting in significantly reduced tumor dispersion. These results resolve the paradoxical production of "anti-migratory" proteoglycans by tumor cells; establish for the first time the entire signaling axis for the proteoglycan brevican in glioma cells; and reveal how this proteoglycan mediates a cooperative interaction between tumor cells and astrocytes that is needed for glioma invasion. These fundamental studies may be leveraged to advance novel anti-invasive strategies that could potentiate the efficacy of current glioma therapies. Citation Format: Somanath Kundu, Hosung Sim, Bin Hu, Mohan S. Nandhu, Russell T. Matthews, Mariano S. Viapiano. A novel mechanism of glioblastoma cell invasion regulated by a neural proteoglycan that activates Src/EGFR signaling and mediates tumor-astroglia cooperation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3148.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-3148
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    Novel Paracrine Modulation of Notch–DLL4 Signaling by Fibulin-3 Promotes Angiogenesis in High-Grade Gliomas
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19 ( 2014-10-01), p. 5435-5448
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19 ( 2014-10-01), p. 5435-5448
    Abstract: High-grade gliomas are characterized by exuberant vascularization, diffuse invasion, and significant chemoresistance, resulting in a recurrent phenotype that makes them impossible to eradicate in the long term. Targeting protumoral signals in the glioma microenvironment could have significant impact against tumor cells and the supporting niche that facilitates their growth. Fibulin-3 is a protein secreted by glioma cells, but absent in normal brain, that promotes tumor invasion and survival. We show here that fibulin-3 is a paracrine activator of Notch signaling in endothelial cells and promotes glioma angiogenesis. Fibulin-3 overexpression increased tumor VEGF levels, microvascular density, and vessel permeability, whereas fibulin-3 knockdown reduced vessel density in xenograft models of glioma. Fibulin-3 localization in human glioblastomas showed dense fiber-like condensations around tumor blood vessels, which were absent in normal brain, suggesting a remarkable association of this protein with tumor endothelium. At the cellular level, fibulin-3 enhanced endothelial cell motility and association to glioma cells, reduced endothelial cell sprouting, and increased formation of endothelial tubules in a VEGF-independent and Notch-dependent manner. Fibulin-3 increased ADAM10/17 activity in endothelial cells by inhibiting the metalloprotease inhibitor TIMP3; this resulted in increased Notch cleavage and increased expression of DLL4 independently of VEGF signaling. Inhibition of ADAM10/17 or knockdown of DLL4 reduced the proangiogenic effects of fibulin-3 in culture. Taken together, these results reveal a novel, proangiogenic role of fibulin-3 in gliomas, highlighting the relevance of this protein as an important molecular target in the tumor microenvironment. Cancer Res; 74(19); 5435–48. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-0685
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 7
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    Fibulin-3 Promotes Glioma Growth and Resistance through a Novel Paracrine Regulation of Notch Signaling
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 15 ( 2012-08-01), p. 3873-3885
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 15 ( 2012-08-01), p. 3873-3885
    Abstract: Malignant gliomas are highly invasive and chemoresistant brain tumors with extremely poor prognosis. Targeting of the soluble factors that trigger invasion and resistance, therefore, could have a significant impact against the infiltrative glioma cells that are a major source of recurrence. Fibulin-3 is a matrix protein that is absent in normal brain but upregulated in gliomas and promotes tumor invasion by unknown mechanisms. Here, we show that fibulin-3 is a novel soluble activator of Notch signaling that antagonizes DLL3, an autocrine inhibitor or Notch, and promotes tumor cell survival and invasion in a Notch-dependent manner. Using a strategy for inducible knockdown, we found that controlled downregulation of fibulin-3 reduced Notch signaling and led to increased apoptosis, reduced self-renewal of glioblastoma-initiating cells, and impaired growth and dispersion of intracranial tumors. In addition, fibulin-3 expression correlated with expression levels of Notch-dependent genes and was a marker of Notch activation in patient-derived glioma samples. These findings underscore a major role for the tumor extracellular matrix in regulating glioma invasion and resistance to apoptosis via activation of the key Notch pathway. More importantly, this work describes a noncanonical, soluble activator of Notch in a cancer model and shows how Notch signaling can be reduced by targeting tumor-specific accessible molecules in the tumor microenvironment. Cancer Res; 72(15); 3873–85. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-1060
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 8
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    Abstract 3797: Validation of a novel antibody against fibulin-3 for targeted therapy of glioblastoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3797-3797
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3797-3797
    Abstract: Glioblastomas (GBM) are highly invasive brain tumors that resist cytotoxic and antiangiogenic therapies, resulting in a high rate of recurrence. Fibulin-3 is an extracellular matrix protein secreted by GBM cells but absent from normal brain. This protein activates Notch signaling to promote tumor invasion and resistance to apoptosis. Conditional knockdown of fibulin-3 reduces GBM growth, invasion and vascularization, thus extending survival. Here we report the initial validation of a function-blocking antibody against this unique GBM target. We first identified the Notch-activating motif of fibulin-3 and developed an immunizing peptide against a key sequence within this motif. A monoclonal antibody generated against this peptide (mAb428.2) showed high affinity for fibulin-3 (Kd 5 nM) and no cross-reactivity against highly homologous fibulin-4 or -5. Antibody mAb428.2 detected fibulin-3 in the stroma and capillaries of human GBM without cross-reactivity against normal brain. The antibody (50-250 μg/ml) blocked the activation of Notch induced by fibulin-3 in GBM cells and caused GBM cell cytotoxicity but had no effects on astrocytes or HEK293 cells. Treatment of mice carrying subcutaneous GBM stem-cell (GSC) derived tumors with mAb428.2 (30 mg/kg IV, q24h x 8 days) resulted in tumor slowdown and extended median survival (47% and 64% in two different GSC models). mAb428.2-treated tumors showed decreased BrdU uptake and increased inflammatory reaction in the tumor stroma (macrophage infiltration and cytokine levels). Mice bearing intracranial tumors did not respond to mAb428.2 when delivered by IV or IP routes, likely due to the inability of the antibody to cross the blood brain barrier. This deficiency was overcome by direct intraparenchymal delivery of the mAb428.2 using chronic infusion (0.3 mg of mAb in 200 μl delivered at 1 μl/h over 7d), which resulted in a 26% increase in median survival. These encouraging results suggest that targeted reagents against fibulin-3 may be of clinical importance for novel combination therapies against GBM. Citation Format: Mohan Sobhana Nandhu, Prajna Behera, Vivek Bhaskaran, Ennio Antonio Chiocca, Mariano S. Viapiano. Validation of a novel antibody against fibulin-3 for targeted therapy of glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3797.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-3797
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 9
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    Abstract 2769: Targeting malignant mesothelioma with an antibody against the tumor extracellular matrix protein fibulin-3
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2769-2769
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2769-2769
    Abstract: Malignant mesothelioma (MM) is an aggressive tumor of mesothelial tissues that has poor prognosis and limited therapeutic options. Pass et al. (N Engl J Med 2012) identified the extracellular matrix protein fibulin-3 as an accurate biomarker of MM progression, which can be detected in the tumor parenchyma and in pleural effusions. Here, we report a systematic study of the mechanisms of fibulin-3 in MM and its value as a molecular target. Fibulin-3 activated canonical NFkB signaling and regulated the expression of NFkB-downstream genes, including the proteases MMP9 and MMP13, and the proinvasive proteins TNC and MLCK. Fibulin-3 knockdown downregulated NFkB signaling, reduced MM cell viability and potentiated the cytotoxicity of cisplatin in vitro. We next developed a function-blocking antibody ("mAb428.2") against an epitope of fibulin-3 required for NFkB activation (Nandhu et al., Clin Cancer Res 2017). This antibody blocked fibulin-3 signaling in vitro and reduced the expression of this protein, as well as NFkB-regulated MMP9, in subcutaneous (sc) MM tumors implanted in nude mice. Next, we treated mice carrying sc or intrapleural models of MM with mAb428.2 or control IgG1 (8x 30 mg/kg, q24h) delivered IV. Our anti-fibulin-3 antibody caused a significant reduction of tumor burden and extension of overall survival in both models. Overall, downregulation and inhibition of fibulin-3 proved a successful approach to enhance MM therapy. Given the value of this protein as a MM biomarker, we expect that detection of fibulin-3 may serve to identify patients with the highest chance to respond to combination therapies including anti-fibulin-3 approaches, achieving maximum therapeutic against these aggressive tumors. Citation Format: Mohan Sobhana Nandhu, Chandra Goparaju, Sharon L. Longo, Harvey I. Pass, Mariano S. Viapiano. Targeting malignant mesothelioma with an antibody against the tumor extracellular matrix protein fibulin-3 [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 2769.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2769
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 10
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    Abstract 2353: Fibulin-3, an extracellular matrix protein, regulates Notch signaling and promotes brain tumor cell invasion and survival
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2353-2353
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2353-2353
    Abstract: Malignant gliomas are the most common primary brain tumors and have extremely poor prognosis. Glioma cell infiltrate into normal neural tissue, escaping conventional chemo-radiotherapy and making tumor relapse almost unavoidable. We have recently characterized a novel extracellular matrix (ECM) protein named fibulin-3, which is highly expressed in gliomas but is absent in normal brain and rarely expressed in other solid tumors. We demonstrated that fibulin-3 regulates the expression of metalloproteases and promotes glioma cell invasion. In addition, this ECM protein increases the resistance of glioma cells to pro-apoptotic treatments, including starvation, oxidative stress and treatment with temozolomide. To further understand the mechanisms of fibulin-3 in gliomas, we investigated several candidate pathways but found no activation of EGFR, MAPK or Akt signaling. Interestingly, fibulin-3 bears significant homology with the Notch ligands from the Delta-like family, which prompted us to study the possible activation of this pathway, which is a critical anti-apoptotic pathway in cancer cells. Surprisingly, we found that fibulin-3 increased cleavage of endogenous Notch-1 in glioma cells as well as activation of a Notch-dependent reporter. In agreement, fibulin-3 expression regulated the levels of the Notch effector Hes-1 both in vitro and in vivo. Moreover, the pro-invasive effect of fibulin-3 in glioma cells was inhibited by pharmacological inhibition of Notch signaling or knockdown of Notch-1. This is potentially a novel mechanism by which tumor-associated ECM molecules can activate Notch signaling and modulate this key pro-tumoral pathway in gliomas. These results underscore the potential of fibulin-3 as a glioma-specific target in the tumor microenvironment. 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 2353. doi:10.1158/1538-7445.AM2011-2353
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2353
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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