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Peter M. Siegel - One of the best experts on this subject based on the ideXlab platform.
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Abstract B11: mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB
Molecular Cancer Research, 2020Co-Authors: Marco Biondini, Matthew G. Annis, April A.n. Rose, Cristiano Ferrario, Rosa Puertollano, Mark Basik, Peter M. SiegelAbstract:The biggest challenge in the effective management of breast cancer is the limited duration of therapeutic benefit that is achieved with the current treatment options. Patients diagnosed with triple-negative breast cancer (TNBC), a type of breast tumor with worst prognoses, are currently treated with surgery, radiation and chemotherapy. Unfortunately, despite initial responses cancer cells become resistant to drugs and tumors relapse. We previously identified the cell surface protein GPNMB as a key mediator of breast cancer metastasis. Recently, an antibody-drug conjugate targeting GPNMB (Cdx-011) was developed that has been tested as single agent for the treatment of metastatic TNBC in a clinical trial. We have recently uncovered a novel response of TNBCs to therapeutic treatments: GPNMB expression is greatly elevated following treatment with mTOR pathway inhibitors (i.e., rapamycin, INK-128, AZD2014 and Torin-1) as well as conventional chemotherapy agents (doxorubicin, paclitaxel or cisplatin) and experimental treatments, i.e., MEK pathway inhibitors. Pharmacologically induced enhancement of GPNMB was also observed in ER+ cancers treated with antiestrogens (i.e., Fulvestrant). Interestingly, tumor cells that developed resistance to chemotherapy or antiestrogens exhibit higher levels of GPNMB. We found that therapy-induced GPNMB upregulation is mediated by the mobilization of the stress-induced MiTF/TFE family of transcription factors. In TNBC cells, mTOR inhibition promotes TFE3 nuclear translocation and GPNMB transcription. In ER+ cells, antiestrogens inactivate mTOR pathway causing TFE3 nucleus localization and GPNMB expression. We are currently conducting preclinical studies to investigate whether the upregulation of GPNMB caused by treatment with mTOR inhibitors could sensitize breast cancer cells to the activity of an antibody-drug conjugate targeting GPNMB (Cdx-011). Citation Format: Marco Biondini, April Rose, Matthew Annis, Cristiano Ferrario, Rosa Puertollano, Mark Basik, Peter Siegel. mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B11.
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GPNMB augments Wnt-1 mediated breast tumor initiation and growth by enhancing PI3K/AKT/mTOR pathway signaling and β-catenin activity.
Oncogene, 2019Co-Authors: Gordana Maric, Matthew G. Annis, Dru Perkins, Patricia A. Macdonald, Caterina Russo, Doris R. Siwak, Gordon B. Mills, Peter M. SiegelAbstract:Glycoprotein Nmb (GPNMB) is overexpressed in triple-negative and basal-like breast cancers and its expression is predictive of poor prognosis within this aggressive breast cancer subtype. GPNMB promotes breast cancer growth, invasion, and metastasis; however, its role in mammary tumor initiation remains unknown. To address this question, we overexpressed GPNMB in the mammary epithelium to generate MMTV/GPNMB transgenic mice and crossed these animals to the MMTV/Wnt-1 mouse model, which is known to recapitulate features of human basal breast cancers. We show that GPNMB alone does not display oncogenic properties; however, its expression dramatically accelerates tumor onset in MMTV/Wnt-1 mice. MMTV/Wnt-1 × MMTV/GPNMB bigenic mice also exhibit a significant increase in the growth rate of established primary tumors, which is attributable to increased proliferation and decreased apoptosis. To elucidate molecular mechanisms underpinning the tumor-promoting effects of GPNMB in this context, we interrogated activated pathways in tumors derived from the MMTV/Wnt-1 and MMTV/Wnt-1 × MMTV/GPNMB mice using RPPA analysis. These data revealed that MMTV/Wnt-1 × MMTV/GPNMB bigenic tumors exhibit a pro-growth signature characterized by elevated PI3K/AKT/mTOR signaling and increased β-catenin activity. Furthermore, we extended these observations to an independent Wnt-1 expressing model of aggressive breast cancer, and confirmed that GPNMB enhances canonical Wnt pathway activation, as evidenced by increased β-catenin transcriptional activity, in breast cancer cells and tumors co-expressing Wnt-1 and GPNMB. GPNMB-dependent engagement of β-catenin occurred, in part, through AKT activation. Taken together, these data ascribe a novel, pro-growth role for GPNMB in Wnt-1 expressing basal breast cancers.
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GPNMB augments wnt 1 mediated breast tumor initiation and growth by enhancing pi3k akt mtor pathway signaling and β catenin activity
Oncogene, 2019Co-Authors: Gordana Maric, Matthew G. Annis, Dru Perkins, Patricia A. Macdonald, Caterina Russo, Doris R. Siwak, Gordon B. Mills, Peter M. SiegelAbstract:Glycoprotein Nmb (GPNMB) is overexpressed in triple-negative and basal-like breast cancers and its expression is predictive of poor prognosis within this aggressive breast cancer subtype. GPNMB promotes breast cancer growth, invasion, and metastasis; however, its role in mammary tumor initiation remains unknown. To address this question, we overexpressed GPNMB in the mammary epithelium to generate MMTV/GPNMB transgenic mice and crossed these animals to the MMTV/Wnt-1 mouse model, which is known to recapitulate features of human basal breast cancers. We show that GPNMB alone does not display oncogenic properties; however, its expression dramatically accelerates tumor onset in MMTV/Wnt-1 mice. MMTV/Wnt-1 × MMTV/GPNMB bigenic mice also exhibit a significant increase in the growth rate of established primary tumors, which is attributable to increased proliferation and decreased apoptosis. To elucidate molecular mechanisms underpinning the tumor-promoting effects of GPNMB in this context, we interrogated activated pathways in tumors derived from the MMTV/Wnt-1 and MMTV/Wnt-1 × MMTV/GPNMB mice using RPPA analysis. These data revealed that MMTV/Wnt-1 × MMTV/GPNMB bigenic tumors exhibit a pro-growth signature characterized by elevated PI3K/AKT/mTOR signaling and increased β-catenin activity. Furthermore, we extended these observations to an independent Wnt-1 expressing model of aggressive breast cancer, and confirmed that GPNMB enhances canonical Wnt pathway activation, as evidenced by increased β-catenin transcriptional activity, in breast cancer cells and tumors co-expressing Wnt-1 and GPNMB. GPNMB-dependent engagement of β-catenin occurred, in part, through AKT activation. Taken together, these data ascribe a novel, pro-growth role for GPNMB in Wnt-1 expressing basal breast cancers.
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GPNMB methylation: a new marker of potentially carcinogenic colon lesions
BMC Cancer, 2018Co-Authors: Hassan Ashktorab, Hamed Rahi, Mehdi Nouraie, Babak Shokrani, Edward Lee, Tahmineh Haydari, Adeyinka O. Laiyemo, Peter M. Siegel, Hassan BrimAbstract:Epigenetic plays an important role in colorectal neoplasia process. There is a need to determine sound biomarkers of colorectal cancer (CRC) progression with clinical and therapeutic implications. Therefore, we aimed to examine the role and methylation status of Glyco Protein Non-Metastatic GPNM B (GPNMB) gene in normal, adenoma and CRC in African American (AA) patients. The methylation status of 13 CpG sites (chr7: 23287345–23,287,426) in GPNMB gene’s promoter, was analyzed by pyrosequencing in human CRC cell lines (HCT116, SW480, and HT29) and microdissected African American paraffin embedded samples (20 normal, 21 non-advanced adenoma (NA), 48 advanced adenoma (AD), and 20 cancer tissues. GPNMB expression was analyzed by immunohistochemistry (IHC) on tissue microarrays (TMA). Correlations between GPNMB methylation and expression with clinicopathological features were analyzed. GPNMB functional analysis was performed in triplicates using cell proliferation, migration and invasion assays in HCT116 colon cell line after stable transfection with a GPNMB-cDNA expression vector. GPNMB methylation was lower in normal mucosa compared to CRC samples (1/20 [5%] vs. 18/20 [90%]; P 0.05) compared to the mock-transfected cells. Our data indicate a high methylation profile leading to a lower GPNMB expression in adenoma and CRC samples. The functional analysis established GPNMB as a potential tumor suppressor gene. As such, GPNMB might be useful as a biomarker of adenomas with high carcinogenic potential.
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Targeting GPNMB with glembatumumab vedotin: Current developments and future opportunities for the treatment of cancer.
Pharmacology & Therapeutics, 2017Co-Authors: April A.n. Rose, Marco Biondini, Rafael Curiel, Peter M. SiegelAbstract:GPNMB has emerged as an immunomodulator and an important positive mediator of tumor progression and metastasis in numerous solid cancers. Tumor intrinsic GPNMB-mediated effects on cellular signaling, coupled with the ability of GPNMB to influence the primary tumor and metastatic microenvironments in a non-cell autonomous fashion, combine to augment malignant cancer phenotypes. In addition, GPNMB is often overexpressed in a variety of cancers, making it an attractive therapeutic target. In this regard, glembatumumab vedotin, an antibody-drug conjugate (ADC) that targets GPNMB, is currently in clinical trials as a single agent in multiple cancers. In this review, we will describe the physiological functions of GPNMB in normal tissues and summarize the processes through which GPNMB augments tumor growth and metastasis. We will review the pre-clinical and clinical development of glembatumumab vedotin, evaluate on-going clinical trials, explore emerging opportunities for this agent in new disease indications and discuss exciting possibilities for this ADC in the context of combination therapies.
April A.n. Rose - One of the best experts on this subject based on the ideXlab platform.
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Abstract B11: mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB
Molecular Cancer Research, 2020Co-Authors: Marco Biondini, Matthew G. Annis, April A.n. Rose, Cristiano Ferrario, Rosa Puertollano, Mark Basik, Peter M. SiegelAbstract:The biggest challenge in the effective management of breast cancer is the limited duration of therapeutic benefit that is achieved with the current treatment options. Patients diagnosed with triple-negative breast cancer (TNBC), a type of breast tumor with worst prognoses, are currently treated with surgery, radiation and chemotherapy. Unfortunately, despite initial responses cancer cells become resistant to drugs and tumors relapse. We previously identified the cell surface protein GPNMB as a key mediator of breast cancer metastasis. Recently, an antibody-drug conjugate targeting GPNMB (Cdx-011) was developed that has been tested as single agent for the treatment of metastatic TNBC in a clinical trial. We have recently uncovered a novel response of TNBCs to therapeutic treatments: GPNMB expression is greatly elevated following treatment with mTOR pathway inhibitors (i.e., rapamycin, INK-128, AZD2014 and Torin-1) as well as conventional chemotherapy agents (doxorubicin, paclitaxel or cisplatin) and experimental treatments, i.e., MEK pathway inhibitors. Pharmacologically induced enhancement of GPNMB was also observed in ER+ cancers treated with antiestrogens (i.e., Fulvestrant). Interestingly, tumor cells that developed resistance to chemotherapy or antiestrogens exhibit higher levels of GPNMB. We found that therapy-induced GPNMB upregulation is mediated by the mobilization of the stress-induced MiTF/TFE family of transcription factors. In TNBC cells, mTOR inhibition promotes TFE3 nuclear translocation and GPNMB transcription. In ER+ cells, antiestrogens inactivate mTOR pathway causing TFE3 nucleus localization and GPNMB expression. We are currently conducting preclinical studies to investigate whether the upregulation of GPNMB caused by treatment with mTOR inhibitors could sensitize breast cancer cells to the activity of an antibody-drug conjugate targeting GPNMB (Cdx-011). Citation Format: Marco Biondini, April Rose, Matthew Annis, Cristiano Ferrario, Rosa Puertollano, Mark Basik, Peter Siegel. mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B11.
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Targeting GPNMB with glembatumumab vedotin: Current developments and future opportunities for the treatment of cancer.
Pharmacology & Therapeutics, 2017Co-Authors: April A.n. Rose, Marco Biondini, Rafael Curiel, Peter M. SiegelAbstract:GPNMB has emerged as an immunomodulator and an important positive mediator of tumor progression and metastasis in numerous solid cancers. Tumor intrinsic GPNMB-mediated effects on cellular signaling, coupled with the ability of GPNMB to influence the primary tumor and metastatic microenvironments in a non-cell autonomous fashion, combine to augment malignant cancer phenotypes. In addition, GPNMB is often overexpressed in a variety of cancers, making it an attractive therapeutic target. In this regard, glembatumumab vedotin, an antibody-drug conjugate (ADC) that targets GPNMB, is currently in clinical trials as a single agent in multiple cancers. In this review, we will describe the physiological functions of GPNMB in normal tissues and summarize the processes through which GPNMB augments tumor growth and metastasis. We will review the pre-clinical and clinical development of glembatumumab vedotin, evaluate on-going clinical trials, explore emerging opportunities for this agent in new disease indications and discuss exciting possibilities for this ADC in the context of combination therapies.
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Abstract P3-07-03: GPNMB activates EGFR to overcome Mek-inhibition: Implications for the development of rational targeted therapy combinations in triple negative breast cancer
Cancer Research, 2017Co-Authors: April A.n. Rose, Matthew G. Annis, Dru Perkins, Peter M. SiegelAbstract:Background: TNBC is an aggressive subtype that constitutes ~15% of all BC. Currently there are no targeted therapies available for patients with. As such, there is much interest in developing targeted therapies for this disease. Recently we identified GPNMB as a transmembrane protein that promotes breast tumor growth and metastasis. CDX-011 is an antibody drug conjugate that targets GPNMB, and has recently shown promising clinical activity in patients with GPNMB+TNBC. In subset analyses of the EMERGE trial, patients with high GPNMB expressing TNBC had a median OS of 10 vs. 5.5 months for CDX011 versus chemotherapy, respectively. Response rates to CDX011 correlated with degree of GPNMB expression. These findings support the hypothesis that TNBC with high GPNMB will respond better to CDX011. As such, we sought to identify therapies with intrinsic activity against TNBC that would also induce GPNMB expression, in order to synergize with CDX-011. We have recently shown that MAPK pathway inhibition induces GPNMB expression in melanoma. Therefore we sought to determine whether Mek inhibition (Mek-i) induced GPNMB in TNBC and the targeted therapies could synergize with CDX-011. Results: We interrogated the TCGA breast datasets to determine whether the MAPK pathway is more frequently altered in TNBC. Indeed, this pathway is altered in 94% of Basal compared to 60% LumA, 83% LumB, 73% Her2 subtypes. Furthermore, we show that a Mek-activation transcriptional signature is significantly higher in basal compared to Her2 or Luminal subtypes. Indeed, we show that Fra, a downstream target of activated Erk, is most highly expressed in BC cells of the basal subtype. We used immunoblot and FACS analysis to assess GPNMB expression in response to Mek-i; trametinib and cobimetinib markedly induced GPNMB protein expression in 12 of the 14 TNBC cell lines tested. Moreover, we show that in the TCGA dataset, low expression of the Mek-activity signature correlates with higher GPNMB, specifically within the basal subtype, thus providing clinical corroboration for our in vitro observations. We go on to show that Mek-i mediated GPNMB up-regulation is regulated by TFE3. We find that EGFR is upregulated in response to Mek inhibition in several TNBC cells. GPNMB heterodimerizes with EGFR in immunoprecipitation experiments. Using siRNA to knockdown GPNMB or ectopic GPNMB overexpression, we found that GPNMB is both necessary and sufficient for enhanced EGFR activation in response to Mek-i in TNBC. Finally, we used CRISPR-CAS9 to delete genomic GPNMB from murine lung-metastatic TNBC cell lines. 533LM2 grow in syngeneic Balb/c mice. Here we show that GPNMB is required for tumor growth and metastasis in vivo . Mek-i slows tumor growth; but the combination of GPNMB deletion with Mek-i led to tumor regression, and significantly impaired tumor growth and metastasis relative to all other groups. Conclusions: Together our data show that the MAPK pathway is hyperactivated in TNBC; inhibiting this pathway impairs tumor growth, but enhances GPNMB, which facilitates mammary tumor growth and metastasis in the setting of Mek-i. These data provide rationale for combined targeting of GPNMB and the MAPK pathway in TNBC. Citation Format: Rose A, Annis M, Perkins D, Siegel P. GPNMB activates EGFR to overcome Mek-inhibition: Implications for the development of rational targeted therapy combinations in triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-03.
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mapk pathway inhibitors sensitize braf mutant melanoma to an antibody drug conjugate targeting GPNMB
Clinical Cancer Research, 2016Co-Authors: April A.n. Rose, Matthew G. Annis, Zhifeng Dong, Marco Biondini, Dennie T Frederick, Lawrence N Kwong, Lynda Chin, Tibor Keler, Thomas Hawthorne, Ian R WatsonAbstract:Purpose: To determine if BRAF and/or MEK inhibitor-induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB. Experimental Design: The TCGA melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot and FACs analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from melanoma patients taken before, during and after disease progression on MAPK inhibitor treatment. Sub-cutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth. Results: A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor-treated melanoma cells and is also elevated in on-treatment versus pre-treatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug-conjugate targeting GPNMB, is effective in causing melanoma regression in pre-clinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone. Conclusions: The combination of MAPK pathway inhibitors with an antibody-drug-conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma.
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Abstract P5-04-03: Targeting glycoprotein non-metastatic B (GPNMB) to overcome EGFR-mediated resistance to Mek inhibition in triple negative breast cancer
Cancer Research, 2016Co-Authors: April A.n. Rose, Matthew G. Annis, Gordana Maric, Peter M. SiegelAbstract:Background: Triple negative breast cancer (TNBC) is an aggressive subtype that constitutes ∼15% of all BC. Currently there are no targeted therapies available for patients with TNBC and these patients have a poor prognosis. As such, there is much interest in developing targeted therapies for this disease. Recently we identified GPNMB as a transmembrane protein that promotes breast tumor growth and metastasis. CDX-011 is an antibody drug conjugate that targets GPNMB, and has recently shown promising clinical activity in patients with GPNMB+TNBC. In subset analyses of the EMERGE trial, patients with high GPNMB expressing TNBC had a median OS of 10 vs. 5.5 months for CDX011 versus chemotherapy, respectively. Response rates to CDX011 correlated with degree of GPNMB expression. These findings support the hypothesis that TNBC with high GPNMB will respond better to CDX011. As such, we sought to identify therapies with intrinsic activity against TNBC that would also induce GPNMB expression, in order to synergize with CDX-011. Recently there has been much interest in targeting the MAPK pathway in TNBC. We have recently shown that MAPK pathway inhibition induces GPNMB expression in melanoma. Therefore we sought to determine whether mek inhibition induced GPNMB in TNBC and the targeted therapies could synergize with CDX-011. Results: We interrogated the TCGA breast dataset to determine whether the MAPK pathway is more frequently altered in TNBC. Indeed, we find that the MAPK pathway is altered in 93% of basal BC compared to 56%, 82%, and 81% of Lum A, LumB, and Her2 subtypes, respectively. We used immunoblot and FACS analysis to assess GPNMB expression in response to MAPK-inhibition. We found that mek inhibitors (trametinib, cobimetinib) markedly induced GPNMB protein expression in several TNBC cell lines. RTK upregulation has been proposed as an adaptive resistance mechanism to mek inhibition in TNBC. Indeed, we find that EGFR is upregulated in response to Mek inhibition in MDA-MB-468 and Hs578T cells. Using shRNA to knockdown GPNMB expression in MDA-MB-468 cells or ectopic GPNMB overexpression in Hs578t cells, we found that GPNMB is both necessary and sufficient for enhanced EGFR activation in response to Mek inhibition in TNBC. Interestingly, we also find that Hs578T cells overexpressing GPNMB show less growth inhibition in response to Mek inhibitors compared to control cells in vitro. These in vitro data are corroborated by our analyses of 1097 breast tumors from the TCGA dataset. GPNMB alterations were found in 7% of all BC and correlates significantly with increased EGFR, Mek and Erk activation. Finally, we are investigating the efficacy of combining trametinib with CDX011 to treat TNBC using in vivo mouse models. Preliminary data from this experiment suggest that MDA-MB-468 tumors treated with both drugs are more growth restricted than tumors treated with either drug alone. Final data will be presented at the meeting. Conclusions: Mek inhibition induces GPNMB expression in TNBC. GPNMB promotes EGFR activation and protects from mek-inhibitor induced growth inhibition. The combination of a mek inhibitor with CDX011 shows promise in pre-clinical models and warrants further investigation in clinical trials. Citation Format: Rose AA, Annis MG, Maric G, Siegel PM. Targeting glycoprotein non-metastatic B (GPNMB) to overcome EGFR-mediated resistance to Mek inhibition in triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-04-03.
Matthew G. Annis - One of the best experts on this subject based on the ideXlab platform.
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Abstract B11: mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB
Molecular Cancer Research, 2020Co-Authors: Marco Biondini, Matthew G. Annis, April A.n. Rose, Cristiano Ferrario, Rosa Puertollano, Mark Basik, Peter M. SiegelAbstract:The biggest challenge in the effective management of breast cancer is the limited duration of therapeutic benefit that is achieved with the current treatment options. Patients diagnosed with triple-negative breast cancer (TNBC), a type of breast tumor with worst prognoses, are currently treated with surgery, radiation and chemotherapy. Unfortunately, despite initial responses cancer cells become resistant to drugs and tumors relapse. We previously identified the cell surface protein GPNMB as a key mediator of breast cancer metastasis. Recently, an antibody-drug conjugate targeting GPNMB (Cdx-011) was developed that has been tested as single agent for the treatment of metastatic TNBC in a clinical trial. We have recently uncovered a novel response of TNBCs to therapeutic treatments: GPNMB expression is greatly elevated following treatment with mTOR pathway inhibitors (i.e., rapamycin, INK-128, AZD2014 and Torin-1) as well as conventional chemotherapy agents (doxorubicin, paclitaxel or cisplatin) and experimental treatments, i.e., MEK pathway inhibitors. Pharmacologically induced enhancement of GPNMB was also observed in ER+ cancers treated with antiestrogens (i.e., Fulvestrant). Interestingly, tumor cells that developed resistance to chemotherapy or antiestrogens exhibit higher levels of GPNMB. We found that therapy-induced GPNMB upregulation is mediated by the mobilization of the stress-induced MiTF/TFE family of transcription factors. In TNBC cells, mTOR inhibition promotes TFE3 nuclear translocation and GPNMB transcription. In ER+ cells, antiestrogens inactivate mTOR pathway causing TFE3 nucleus localization and GPNMB expression. We are currently conducting preclinical studies to investigate whether the upregulation of GPNMB caused by treatment with mTOR inhibitors could sensitize breast cancer cells to the activity of an antibody-drug conjugate targeting GPNMB (Cdx-011). Citation Format: Marco Biondini, April Rose, Matthew Annis, Cristiano Ferrario, Rosa Puertollano, Mark Basik, Peter Siegel. mTOR pathway inhibition induces GPNMB expression and sensitizes breast cancer cells to an antibody-drug conjugate targeting GPNMB [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B11.
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GPNMB augments Wnt-1 mediated breast tumor initiation and growth by enhancing PI3K/AKT/mTOR pathway signaling and β-catenin activity.
Oncogene, 2019Co-Authors: Gordana Maric, Matthew G. Annis, Dru Perkins, Patricia A. Macdonald, Caterina Russo, Doris R. Siwak, Gordon B. Mills, Peter M. SiegelAbstract:Glycoprotein Nmb (GPNMB) is overexpressed in triple-negative and basal-like breast cancers and its expression is predictive of poor prognosis within this aggressive breast cancer subtype. GPNMB promotes breast cancer growth, invasion, and metastasis; however, its role in mammary tumor initiation remains unknown. To address this question, we overexpressed GPNMB in the mammary epithelium to generate MMTV/GPNMB transgenic mice and crossed these animals to the MMTV/Wnt-1 mouse model, which is known to recapitulate features of human basal breast cancers. We show that GPNMB alone does not display oncogenic properties; however, its expression dramatically accelerates tumor onset in MMTV/Wnt-1 mice. MMTV/Wnt-1 × MMTV/GPNMB bigenic mice also exhibit a significant increase in the growth rate of established primary tumors, which is attributable to increased proliferation and decreased apoptosis. To elucidate molecular mechanisms underpinning the tumor-promoting effects of GPNMB in this context, we interrogated activated pathways in tumors derived from the MMTV/Wnt-1 and MMTV/Wnt-1 × MMTV/GPNMB mice using RPPA analysis. These data revealed that MMTV/Wnt-1 × MMTV/GPNMB bigenic tumors exhibit a pro-growth signature characterized by elevated PI3K/AKT/mTOR signaling and increased β-catenin activity. Furthermore, we extended these observations to an independent Wnt-1 expressing model of aggressive breast cancer, and confirmed that GPNMB enhances canonical Wnt pathway activation, as evidenced by increased β-catenin transcriptional activity, in breast cancer cells and tumors co-expressing Wnt-1 and GPNMB. GPNMB-dependent engagement of β-catenin occurred, in part, through AKT activation. Taken together, these data ascribe a novel, pro-growth role for GPNMB in Wnt-1 expressing basal breast cancers.
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GPNMB augments wnt 1 mediated breast tumor initiation and growth by enhancing pi3k akt mtor pathway signaling and β catenin activity
Oncogene, 2019Co-Authors: Gordana Maric, Matthew G. Annis, Dru Perkins, Patricia A. Macdonald, Caterina Russo, Doris R. Siwak, Gordon B. Mills, Peter M. SiegelAbstract:Glycoprotein Nmb (GPNMB) is overexpressed in triple-negative and basal-like breast cancers and its expression is predictive of poor prognosis within this aggressive breast cancer subtype. GPNMB promotes breast cancer growth, invasion, and metastasis; however, its role in mammary tumor initiation remains unknown. To address this question, we overexpressed GPNMB in the mammary epithelium to generate MMTV/GPNMB transgenic mice and crossed these animals to the MMTV/Wnt-1 mouse model, which is known to recapitulate features of human basal breast cancers. We show that GPNMB alone does not display oncogenic properties; however, its expression dramatically accelerates tumor onset in MMTV/Wnt-1 mice. MMTV/Wnt-1 × MMTV/GPNMB bigenic mice also exhibit a significant increase in the growth rate of established primary tumors, which is attributable to increased proliferation and decreased apoptosis. To elucidate molecular mechanisms underpinning the tumor-promoting effects of GPNMB in this context, we interrogated activated pathways in tumors derived from the MMTV/Wnt-1 and MMTV/Wnt-1 × MMTV/GPNMB mice using RPPA analysis. These data revealed that MMTV/Wnt-1 × MMTV/GPNMB bigenic tumors exhibit a pro-growth signature characterized by elevated PI3K/AKT/mTOR signaling and increased β-catenin activity. Furthermore, we extended these observations to an independent Wnt-1 expressing model of aggressive breast cancer, and confirmed that GPNMB enhances canonical Wnt pathway activation, as evidenced by increased β-catenin transcriptional activity, in breast cancer cells and tumors co-expressing Wnt-1 and GPNMB. GPNMB-dependent engagement of β-catenin occurred, in part, through AKT activation. Taken together, these data ascribe a novel, pro-growth role for GPNMB in Wnt-1 expressing basal breast cancers.
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Abstract P3-07-03: GPNMB activates EGFR to overcome Mek-inhibition: Implications for the development of rational targeted therapy combinations in triple negative breast cancer
Cancer Research, 2017Co-Authors: April A.n. Rose, Matthew G. Annis, Dru Perkins, Peter M. SiegelAbstract:Background: TNBC is an aggressive subtype that constitutes ~15% of all BC. Currently there are no targeted therapies available for patients with. As such, there is much interest in developing targeted therapies for this disease. Recently we identified GPNMB as a transmembrane protein that promotes breast tumor growth and metastasis. CDX-011 is an antibody drug conjugate that targets GPNMB, and has recently shown promising clinical activity in patients with GPNMB+TNBC. In subset analyses of the EMERGE trial, patients with high GPNMB expressing TNBC had a median OS of 10 vs. 5.5 months for CDX011 versus chemotherapy, respectively. Response rates to CDX011 correlated with degree of GPNMB expression. These findings support the hypothesis that TNBC with high GPNMB will respond better to CDX011. As such, we sought to identify therapies with intrinsic activity against TNBC that would also induce GPNMB expression, in order to synergize with CDX-011. We have recently shown that MAPK pathway inhibition induces GPNMB expression in melanoma. Therefore we sought to determine whether Mek inhibition (Mek-i) induced GPNMB in TNBC and the targeted therapies could synergize with CDX-011. Results: We interrogated the TCGA breast datasets to determine whether the MAPK pathway is more frequently altered in TNBC. Indeed, this pathway is altered in 94% of Basal compared to 60% LumA, 83% LumB, 73% Her2 subtypes. Furthermore, we show that a Mek-activation transcriptional signature is significantly higher in basal compared to Her2 or Luminal subtypes. Indeed, we show that Fra, a downstream target of activated Erk, is most highly expressed in BC cells of the basal subtype. We used immunoblot and FACS analysis to assess GPNMB expression in response to Mek-i; trametinib and cobimetinib markedly induced GPNMB protein expression in 12 of the 14 TNBC cell lines tested. Moreover, we show that in the TCGA dataset, low expression of the Mek-activity signature correlates with higher GPNMB, specifically within the basal subtype, thus providing clinical corroboration for our in vitro observations. We go on to show that Mek-i mediated GPNMB up-regulation is regulated by TFE3. We find that EGFR is upregulated in response to Mek inhibition in several TNBC cells. GPNMB heterodimerizes with EGFR in immunoprecipitation experiments. Using siRNA to knockdown GPNMB or ectopic GPNMB overexpression, we found that GPNMB is both necessary and sufficient for enhanced EGFR activation in response to Mek-i in TNBC. Finally, we used CRISPR-CAS9 to delete genomic GPNMB from murine lung-metastatic TNBC cell lines. 533LM2 grow in syngeneic Balb/c mice. Here we show that GPNMB is required for tumor growth and metastasis in vivo . Mek-i slows tumor growth; but the combination of GPNMB deletion with Mek-i led to tumor regression, and significantly impaired tumor growth and metastasis relative to all other groups. Conclusions: Together our data show that the MAPK pathway is hyperactivated in TNBC; inhibiting this pathway impairs tumor growth, but enhances GPNMB, which facilitates mammary tumor growth and metastasis in the setting of Mek-i. These data provide rationale for combined targeting of GPNMB and the MAPK pathway in TNBC. Citation Format: Rose A, Annis M, Perkins D, Siegel P. GPNMB activates EGFR to overcome Mek-inhibition: Implications for the development of rational targeted therapy combinations in triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-03.
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mapk pathway inhibitors sensitize braf mutant melanoma to an antibody drug conjugate targeting GPNMB
Clinical Cancer Research, 2016Co-Authors: April A.n. Rose, Matthew G. Annis, Zhifeng Dong, Marco Biondini, Dennie T Frederick, Lawrence N Kwong, Lynda Chin, Tibor Keler, Thomas Hawthorne, Ian R WatsonAbstract:Purpose: To determine if BRAF and/or MEK inhibitor-induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB. Experimental Design: The TCGA melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot and FACs analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from melanoma patients taken before, during and after disease progression on MAPK inhibitor treatment. Sub-cutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth. Results: A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor-treated melanoma cells and is also elevated in on-treatment versus pre-treatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug-conjugate targeting GPNMB, is effective in causing melanoma regression in pre-clinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone. Conclusions: The combination of MAPK pathway inhibitors with an antibody-drug-conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma.
Hideaki Hara - One of the best experts on this subject based on the ideXlab platform.
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GPNMB Induces BiP Expression by Enhancing Splicing of BiP Pre-mRNA during the Endoplasmic Reticulum Stress Response
Scientific Reports, 2017Co-Authors: Yasuhiro Noda, Yusuke Nakano, Kazuhiro Tsuruma, Masamitsu Shimazawa, Yuki Nagahara, Hirotaka Tanaka, Mitsue Ishisaka, Masafumi Takata, Hideaki HaraAbstract:Glycoprotein nonmetastatic melanoma protein B (GPNMB) has a neuroprotective effect against neuronal cell death caused by the accumulation of abnormal mutated proteins. It is known that the accumulation of pathological proteins induces endoplasmic-reticulum (ER) stress leading to cell damage. The aim of this study was to determine the role of GPNMB in the ER stress response. GPNMB was greatly up-regulated by thapsigargin-induced ER stress. Under the ER stress conditions, GPNMB relocated to the nucleus and specifically up-regulated expression of BiP at the mRNA level by promoting the BiP pre-mRNA splicing, not through the pathways initiated by the three major transducers of the unfolded protein response: IRE1, PERK, and ATF6. Furthermore, we found that the protein level of BiP and the infarction were increased and attenuated, respectively, in GPNMB-transgenic mice after occlusion of the middle cerebral artery, in comparison with wild-type mice. Thus, our findings indicate that GPNMB enhances the BiP expression by promoting the splicing (thereby preventing cell death caused by ER stress) and could be a therapeutic target in ER stress-related disorders.
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GPNMB ameliorates mutant tdp 43 induced motor neuron cell death
Journal of Neuroscience Research, 2017Co-Authors: Yuki Nagahara, Kazuhiro Tsuruma, Masamitsu Shimazawa, Kazuki Ohuchi, Junko Ito, Hitoshi Takahashi, Akiyoshi Kakita, Hideaki HaraAbstract:Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. © 2016 Wiley Periodicals, Inc.
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GPNMB ameliorates mutant TDP‐43‐induced motor neuron cell death
Journal of Neuroscience Research, 2016Co-Authors: Yuki Nagahara, Kazuhiro Tsuruma, Masamitsu Shimazawa, Kazuki Ohuchi, Junko Ito, Hitoshi Takahashi, Akiyoshi Kakita, Hideaki HaraAbstract:Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. © 2016 Wiley Periodicals, Inc.
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Glycoprotein nonmetastatic melanoma protein B (GPNMB) promotes the progression of brain glioblastoma via Na+/K+-ATPase.
Biochemical and biophysical research communications, 2016Co-Authors: Y. Ono, Kazuhiro Tsuruma, Masamitsu Shimazawa, Toru Iwama, Shinsuke Chiba, Hirohito Yano, Noriyuki Nakayama, Masanao Saio, Hideaki HaraAbstract:Glycoprotein nonmetastatic melanoma protein B (GPNMB), which is involved in invasion and metastasis, was found to be overexpressed in various cancers. High levels of GPNMB and Na+/K+-ATPase α subunits are associated with a poor prognosis in glioblastoma patients. We showed that GPNMB interacts with Na+/K+-ATPase α subunits to activate PI3K/Akt and MEK/ERK pathways. However, it remains unclear whether the interaction of GPNMB and Na+/K+-ATPase α subunits is involves in progression of glioma. The tumor size induced by the injection of glioma GL261 cells was larger in transgenic mice overexpressing GPNMB when compared with wild-type mice. Additionally, the interaction of GPNMB and Na+/K+-ATPase α subunits was identified in the murine glioma model and in the tumors of glioblastoma patients. Ouabain, a Na+/K+-ATPase inhibitor, suppressed the glioma growth induced by the injection of glioma cells in the transgenic mice overexpressing GPNMB and blocked the GPNMB-induced migration of glioma cells. These findings indicate that GPNMB promotes glioma growth via Na+/K+-ATPase α subunits. Thus, the interaction between GPNMB and Na+, K+-ATPase α subunits represents a novel therapeutic target for the treatment of brain glioblastomas.
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The effect of GPNMB on muscular atrophy caused by ALS
2015Co-Authors: Yuki Nagahara, Kazuhiro Tsuruma, Masamitsu Shimazawa, Hideaki HaraAbstract:Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by the degeneration of motor neurons and subsequent muscular defects. Recent findings have highlighted the contribution of intrinsic skeletal muscle defects to ALS. Research focusing on skeletal muscle disorders might therefore offer alternative routes to the development of new therapeutic options for the treatment of ALS. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane protein also known as osteoactivin (OA) and dendritic cell-heparin integrin ligand (DC-HIL). GPNMB exerts a protective effect on the central nervous system, and it has been shown to improve memory and to help recovery from reperfusion injury following brain ischemia. In ALS model mice, overexpression of GPNMB prevents motor neuron death and reduces denervation of neuromuscular junctions and atrophy of the skeletal muscles, resulting in a delayed onset of ALS and a longer life span of the animals. When directly injected into skeletal muscle, GPNMB also helps prevent injury of myofibers. These data indicate that GPNMB has a dual site of action against the central nervous system and directly skeletal muscle. Here, we review and highlight recent findings on the effect of GPNMB against ALS, and we discuss remaining challenges of the field and the possible therapeutic applications of GPNMB.
Fayez Safadi - One of the best experts on this subject based on the ideXlab platform.
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ab0103 a novel protective role of GPNMB osteoactivin in post traumatic osteoarthritis
Annals of the Rheumatic Diseases, 2019Co-Authors: Asaad Al Adlaan, Nazar J Hussein, Fatima A Jaber, Fayez SafadiAbstract:Background: Osteoarthritis (OA) is a chronic joint disease causes irreversible damage to the articular cartilage resulting in loss of joint function and subchondral bone remodeling. There is no cure for OA and currently the available treatment like pain management, and joint replacement surgery is used to treat this disease. GPNMB/Osteoactivin is a type-I transmembrane protein plays a vital role in osteogenesis and bone remodeling, Objectives: Howver, the function of GPNMB/Osteoactivin in chondrogenesis and cartilage repair is unknown. Hence, in this study, we examined the role of GPNMB/Osteoactivin using post-traumatic osteoarthritis model and ex vivo chondrocytes cell culture and assessing the effects of GPNMB/Osteoactivin as anti-inflammatory factor in chondrocytes. Methods: We first examined the expression GPNMB/Osteoactivin in noramal cartilage. Next, we assessed the effects of recombinant GPNMB/Osteoactivin on mouse primary chondrocytes profeliation/viabiltiy and extracellular matrix marekrs. Results: We founad that GPNMB/Osteoactivin treatment did not have any effect on cell prolfieration/viability, howwever, there was an increased in Colllagen Type II and aggrecan expression in a dose- and time-dependent manner. These data sugges that GPNMB/Osteoactivin palys a role in cartilage maintainance. Next we determined whether GPNMB/Osteoactivin contributes to the OA disease progression. Human osteoarthritic damaged and undamaged cartilage harvested following knee replacement were used to examine GPNMB/Osteoactivin exmression and founad that GPNMB/Osteoactivin mRNA was 6-7-fold increased in damaged compared to undamaged cartilage. Similar results were obtained from mouse primary chondrocytes treated with IL1-b and showed a significant increase (4-fold) in GPNMB/Osteoactivin mRNA compared to untreated control. Next, we evalauted the effects of GPNMB/Osteoactivin deficiency on the OA progression usign the DMM model. GPNMB/Osteoactivin muntat (DBA/2J) mice showed significant increased in OARSI scores compared to WT mice. Conclusion: Taken together, these data are the first to report a role for GPNMB/Osteoactivin in cartilage maintanance and protection again the prgoression of OA. References [1] The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Methods in Molecular Biology: Osteoporosis and Osteoarthritis. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: A disease of the joint as an organ. Arthritis and Rheumatism. 2012. pp. 1697–1707. [2] Zhou, L., Zhuo, H., Ouyang, H., Liu, Y., Yuan, F., Sun, L.,. .. & Liu, H. (2017). Glycoprotein non-metastatic melanoma protein b (GPNMB) is highly expressed in macrophages of acute injured kidney and promotes M2 macrophages polarization. Cellular immunology, 316, 53-60. [3] Ripoll, V.M., et al., GPNMB is induced in macrophages by IFN-gamma and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses. J Immunol, 2007. 178(10): p. 655766. [4] Karlsson C, Dehne T, Lindahl A, Brittberg M, Pruss A, Sittinger M, Ringe J. Genome-wide expression profiling reveals new candidate genes associated with osteoarthritis. Osteoarthritis and Cartilage. 2010Apr1;18(4):581-92. Acknowledgement: This research was funded in part by the Cook Research Fund, Summa Heatlh System and Ohio Department of Education Disclosure of Interests: None declared
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ab0078 the therapeutic effect of GPNMB in a traumatically induced osteoarthritic model
Annals of the Rheumatic Diseases, 2019Co-Authors: Bryson P Cook, Asaad Al Adlaan, Mathew Desanto, Rama Safadi, Salvatore J Frangiamore, Fayez SafadiAbstract:Background: Osteoarthritis is a severe joint disease that affects millions of people. At this time, the current treatment for osteoarthritis is total joint reconstruction surgery. GPNMB plays a key role in bone remodeling and bone growth. Data from our lab suggested that GPNMB is positive regulator of osteoblastogenesis and a negative regulator of osteoclastogenesis. Objectives: The role of GPNMB in cartilage has not been investigated before. In this study we examined the therepaeutic effects of GPNMB on damaged cartilage using post-traumatic osteoarthritic mouse model. Methods: The destabilization of the medial meniscus (DMM) surgery in mice has been found to be an excellent model for studying post-traumatic osteoarthritis. We performed the DMM surgery on 21 C57/BL6 mice. These mice were divided into three intra-articular injection treatment groups consisting of a control, low dose GPNMB, and high dose GPNMB. These mice were divided into three intra-articular injection treatment groups consisting of a control, low dose GPNMB, and high dose GPNMB. Moderate to severe osteoarthritis develops around six to eight weeks with this model. Results: Here we present that damaged human cartilage has significantly higher levels of GPNMB compared to undamaged cartilage. In addition, human osteoarthritic chondrocytes treated with GPNMB showed a protective response to inflammation induced by IL1-beta. In this study, we examined whether recombinant GPNMB has an anti-inflammatory effect in a model of post-traumatic osteoarthritis. Based on studies performed in our lab, we expected cartilage degeneration to be dramatically decreased in response to the therapeutic effects of GPNMB. A protective factor against osteoarthritis progression, GPNMB-injected mice had significantly reduced cartilage damage and OARSI scores in comparison to the control group, proving GPNMB a promising therapy in lieu of total joint reconstruction. GPNMB-injected mice also had reduced expression of IL-6 and MMP13 but significantly increased expression of aggrecan in comparison to control mice. Conclusion: Our data clearly showed that GPNMB has therapeutics anti-inflammatory effects on protecting cartilage damaged. Hence, future studies will be directed towards examining the therapeutic effects of GPNMB on larger animal models for osteoarthritis. Given the remarkable ability of GPNMB to reduce expression of key inflammatory markers, we conducted this study to reveal GPNMB therapeutic effects in traumatically-induced osteoarthritis. References [1] The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Methods in Molecular Biology: Osteoporosis and Osteoarthritis. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: A disease of the joint as an organ.Arthritis and Rheumatism. 2012. pp. 1697–1707. [2] Zhou, L., Zhuo, H., Ouyang, H., Liu, Y., Yuan, F., Sun, L.,. .. & Liu, H. (2017). Glycoprotein non-metastatic melanoma protein b (GPNMB) is highly expressed in macrophages of acute injured kidney and promotes M2 macrophages polarization. Cellular immunology, 316, 53-60. [3] Ripoll, V.M., et al., GPNMB is induced in macrophages by IFN-gamma and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses. J Immunol, 2007. 178(10): p.655766. [4] Karlsson C, Dehne T, Lindahl A, Brittberg M, Pruss A, Sittinger M, Ringe J. Genome-wide expression profiling reveals new candidate genes associated with osteoarthritis. Osteoarthritis and Cartilage. 2010Apr1;18(4):581-92. Disclosure of Interests: None declared
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AB0103 A NOVEL PROTECTIVE ROLE OF GPNMB/OSTEOACTIVIN IN POST-TRAUMATIC OSTEOARTHRITIS
Abstracts Accepted for Publication, 2019Co-Authors: Asaad Al Adlaan, Nazar J Hussein, Fatima A Jaber, Fayez SafadiAbstract:Background: Osteoarthritis (OA) is a chronic joint disease causes irreversible damage to the articular cartilage resulting in loss of joint function and subchondral bone remodeling. There is no cure for OA and currently the available treatment like pain management, and joint replacement surgery is used to treat this disease. GPNMB/Osteoactivin is a type-I transmembrane protein plays a vital role in osteogenesis and bone remodeling, Objectives: Howver, the function of GPNMB/Osteoactivin in chondrogenesis and cartilage repair is unknown. Hence, in this study, we examined the role of GPNMB/Osteoactivin using post-traumatic osteoarthritis model and ex vivo chondrocytes cell culture and assessing the effects of GPNMB/Osteoactivin as anti-inflammatory factor in chondrocytes. Methods: We first examined the expression GPNMB/Osteoactivin in noramal cartilage. Next, we assessed the effects of recombinant GPNMB/Osteoactivin on mouse primary chondrocytes profeliation/viabiltiy and extracellular matrix marekrs. Results: We founad that GPNMB/Osteoactivin treatment did not have any effect on cell prolfieration/viability, howwever, there was an increased in Colllagen Type II and aggrecan expression in a dose- and time-dependent manner. These data sugges that GPNMB/Osteoactivin palys a role in cartilage maintainance. Next we determined whether GPNMB/Osteoactivin contributes to the OA disease progression. Human osteoarthritic damaged and undamaged cartilage harvested following knee replacement were used to examine GPNMB/Osteoactivin exmression and founad that GPNMB/Osteoactivin mRNA was 6-7-fold increased in damaged compared to undamaged cartilage. Similar results were obtained from mouse primary chondrocytes treated with IL1-b and showed a significant increase (4-fold) in GPNMB/Osteoactivin mRNA compared to untreated control. Next, we evalauted the effects of GPNMB/Osteoactivin deficiency on the OA progression usign the DMM model. GPNMB/Osteoactivin muntat (DBA/2J) mice showed significant increased in OARSI scores compared to WT mice. Conclusion: Taken together, these data are the first to report a role for GPNMB/Osteoactivin in cartilage maintanance and protection again the prgoression of OA. References [1] The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Methods in Molecular Biology: Osteoporosis and Osteoarthritis. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: A disease of the joint as an organ. Arthritis and Rheumatism. 2012. pp. 1697–1707. [2] Zhou, L., Zhuo, H., Ouyang, H., Liu, Y., Yuan, F., Sun, L.,. .. & Liu, H. (2017). Glycoprotein non-metastatic melanoma protein b (GPNMB) is highly expressed in macrophages of acute injured kidney and promotes M2 macrophages polarization. Cellular immunology, 316, 53-60. [3] Ripoll, V.M., et al., GPNMB is induced in macrophages by IFN-gamma and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses. J Immunol, 2007. 178(10): p. 655766. [4] Karlsson C, Dehne T, Lindahl A, Brittberg M, Pruss A, Sittinger M, Ringe J. Genome-wide expression profiling reveals new candidate genes associated with osteoarthritis. Osteoarthritis and Cartilage. 2010Apr1;18(4):581-92. Acknowledgement: This research was funded in part by the Cook Research Fund, Summa Heatlh System and Ohio Department of Education Disclosure of Interests: None declared
