| 研究課題/領域番号 |
24591382
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| 研究機関 | 東京大学 |
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研究代表者 |
HEISSIG Beate 東京大学, 医科学研究所, 准教授 (30372931)
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| キーワード | 生体分子 / 細胞・組織 / 発言制御 / 酵素 |
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| 研究概要 |
Multiple myeloma (MM) is a B-cell malignancy characterized by the monoclonal proliferation of plasma cells (PCs) in the bone marrow (BM). Over the last year we have established various mouse models of MM including a xenograft and allogeneic mouse model in order to test drugs to prevent disease progression. We can show that the protease MT1-MMP, but also other proteases are expressed in MM cells or its surrounding cells in vitro and in vivo. Because various proteases seemed to be driving MM disease progression we decided to test a small molecule that targets proteases upstream of the proteases found in MM models. This inhibitor can not only impair the activity of MT1-MMP, but also other MMPs known to be involved in the pathogenesis of MM. Preliminary data indicate that this protease inhibitor can prolong survival in murine xenograft and allograft models of MM. We propose that targeting this protease can be a novel therapeutic target for MM.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
We first established that MT1-MMP (and as has been reported by others already of matrix metalloproteinases like MMP-9, MMP-2 and ADAM-9) is expressed in MM cells and also stromal cell lines. We then went on test deficiency of MT1-MMP in stromal cells and the role of stromal-cell derived MT1-MMP for cell growth in vitro. We identified impaired release of some critical growth factors for MM growth in coculture system. Then we set up two murine xenograft models. We were able to show that MM cell growth resulted in the demise of the animals. In addition, we established certain clinical parameters (anemia, bone lesion monitoring using a luciferase expressing MM cells) to monitor drug efficiency in further treatment studies. We similarly established a syngenic mouse model of MM to study the interactions of critical growth factors in the microenvironment of MM cells.
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| 今後の研究の推進方策 |
We initially proposed the use of MT1-MMP specific antibodies to control MM growth. Our data indicated that aside from MT1-MMP other proteases are similarly important for MM growth. We therefore decided to test a small molecule that targets MT1-MMP and other protesases by suppressing their conversion from its inactive into its active form. During the following year, we are planning to use both the murine xenograft and syngenic MM model to test small molecules to target MT1-MMP via suppression of a serine protease known to control the activity of other proteases. We have preliminary data in mice showing that this small molecule reduces the tumor burden in mice. We also try to establish the in vivo targets of this molecule. MT1-MMP has been shown to be involved in the posttranslational modification of various critical target molecules important for MM growth in vitro. We will try to understand the mechanism and downstream targets how the small molecule can control MM growth in vivo and in vitro.
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