Regulation of multiple myeloma by S100A9 protein

 描述（由申请人提供）：多发性骨髓瘤（MM）是一种毁灭性的骨髓（BM）癌症，尽管出现了新的治疗方法，但仍然具有一致的致命性。肿瘤微环境通过对肿瘤细胞与周围BM细胞之间的相互作用知之甚少来促进肿瘤生长和对化疗的抵抗。我们最近已经证明，骨髓来源的抑制细胞群参与MM进展的调节。这些细胞大量产生促炎蛋白S100 A9。我们的初步数据表明，这种蛋白质调节MM的生存和生长，我们假设这种作用至少部分是由S100 A9在增加巨核细胞生成中的直接作用介导的，并且巨核细胞和血小板的血管生成因子的产生增加导致BM血管生成增加和肿瘤进展。我们建议通过确定S100 A9对巨核细胞的分子效应和通过在MM模型中测试新型S100 A9抑制剂来测试这一假设，以观察其是否减少巨核细胞生成和血管生成，从而改善MM结果。具体目标1：具体目标1。明确S100 A9对巨核细胞作用的分子机制;探讨S100 A9作为MM治疗新靶点的作用。

 DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a devastating bone marrow (BM) cancer that remains uniformly fatal despite the emergence of novel therapeutics. The tumor microenvironment promotes tumor growth and resistance to chemotherapy through poorly understood interactions between tumor cells and the surrounding BM cells. We have recently demonstrated that a population of BM myeloid-derived suppressor cells is involved in regulation of MM progression. These cells abundantly produce the pro-inflammatory protein S100A9. Our preliminary data indicate that this protein regulates MM survival and growth, and we hypothesize that this effect is at least partially mediated by a direct effect of S100A9 in increasing megakaryopoiesis, and that increased production of angiogenic factors by megakaryocytes and platelets leads to increased BM angiogenesis and tumor progression. We propose to test this hypothesis by determining the molecular effects of S100A9 on megakaryocytes and by testing a novel S100A9 inhibitor in models of MM to see if it reduces megakaryopoiesis and angiogenesis and thereby improves MM outcomes. The following specific aims will be addressed: Specific Aim 1. To determine the molecular mechanisms underlying the effect of S100A9 on megakaryocytes; Specific Aim 2. To investigate the role of S100A9 as a novel therapeutic target in MM.