Myeloma-Microenvironment Interaction Dynamics

描述(申请人提供)：骨髓瘤的特征是恶性浆细胞在骨髓中聚集，并伴有严重的骨病。在美国，骨髓瘤每年折磨着14,000多人；尽管治疗方法取得了进步，骨髓瘤仍然是无法治愈的，这突显了为这种疾病开发新的干预措施的重要性。我们证明了骨髓瘤疾病和肿瘤进展之间的相互依存关系。因此，我们提出了一种创新的治疗模式，通过刺激骨形成，增加抗肿瘤成骨因子，以及阻断促进骨髓瘤的破骨因子的活性，为骨髓瘤创造一个不适宜居住的骨髓环境。临床观察和我们先前和初步的研究表明，成骨细胞抑制骨髓瘤的生长，成骨细胞激活剂在体内诱导骨形成的同时也减轻了骨髓瘤的负担，这一治疗理念得到了支持。此外，成骨细胞产生高水平的富含小亮氨酸的蛋白多糖(SLRPs)，这是正确的骨重建所必需的，尤其是对某些类型的肿瘤也有抑制作用；我们的初步研究表明，SLRPs抑制骨髓瘤的生长。我们还发现破骨细胞通过物理接触支持骨髓瘤的生长，我们发现成纤维细胞激活因子(FAP)是参与这一过程的关键微环境因子。我们的总体假设是骨髓瘤骨中的破骨细胞上调的因子促进骨髓瘤细胞的存活，而成骨细胞产生的骨构建因子否定了骨髓瘤的进展。我们将利用我们独特的体内和体外系统治疗原发性骨髓瘤，以研究三个特定的目标。我们将(目标1)确定SLRPs在成骨细胞诱导的骨髓瘤生长抑制中的作用，并揭示这些蛋白多糖的体内外抗骨髓瘤的分子机制。我们将测试封闭SLRPs对成骨细胞诱导的骨髓瘤生长抑制的作用，揭示SLRPs的分子机制，并测试其抗骨髓瘤的效果。我们将(目的2)确定强大的成骨细胞激活因子Dickkopf-1(Dkk1)中和抗体、甲状旁腺激素(PTH)和Bortezomib对原发骨髓瘤SCID-Rab小鼠骨髓瘤骨病和骨髓瘤发生发展的影响。我们将(目标3)确定FAP在骨髓瘤发病机制中的作用以及作为一种潜在的微环境靶向治疗；利用重组FAP、特异性FAP抑制剂和短干扰RNA方法，我们将揭示FAP在体外和体内对骨髓瘤进展的直接和间接影响。这项研究的工作将验证与破骨细胞激活相关的新的微环境靶向治疗，并探索使用骨合成代谢药物和SLRP作为提高患者生活质量和控制骨髓瘤的有效和安全的策略。 项目简介：恶性骨髓瘤细胞表现在骨髓中，并导致严重的、疼痛的骨病。我们的主要目标是通过控制骨髓瘤引起的骨破坏，为肿瘤细胞创造一个不利的环境。我们的研究将增加对骨髓瘤发病机制的了解，这将有助于开发同时治疗骨髓瘤疾病和肿瘤进展的新方法，改善患者的生活质量，并防止有患这种不治之症风险的个人发生骨髓瘤。

DESCRIPTION (provided by applicant): Myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow and is accompanied by severe bone disease. Myeloma afflicts more than 14,000 people in the US each year; despite advances in treatment, myeloma remains incurable, highlighting the importance of developing novel interventions for this disease. We demonstrated the interdependence between myeloma bone disease and tumor progression. Therefore, we propose an innovative treatment paradigm based on creating an inhospitable bone marrow environment for myeloma through stimulating bone formation, increasing antitumor osteoblastic factors, and blocking activity of osteoclastic factors that promote myeloma. This therapeutic concept is supported by clinical observations and by our previous and preliminary studies demonstrating that osteoblasts inhibit myeloma growth and that osteoblast-activating agents induce bone formation while also reducing myeloma burden in vivo. Moreover, osteoblasts produce high levels of small-leucine-rich-proteoglycans (SLRPs), which are essential for proper bone remodeling and, notably, also inhibit some tumor types; our preliminary study revealed that SLRPs suppress myeloma growth. We also showed that osteoclasts support myeloma growth via physical contact, and we identified fibroblast activation factor (FAP) as a critical microenvironmental factor involved in this processes. Our overall hypothesis is that factors upregulated on osteoclasts in myelomatous bone promote myeloma cell survival and that bone-building factors produced by osteoblasts negate myeloma progression. We will exploit our unique in vivo and ex vivo systems for primary myeloma to study three Specific Aims. We will (Aim 1) determine the involvement of SLRPs in osteoblast-induced myeloma growth inhibition and unravel anti-myeloma molecular mechanisms of these proteoglycans ex vivo and in vivo. We will test the effect of blocking SLRPs on osteoblast-induced myeloma growth inhibition, unravel SLRPs molecular mechanisms, and test their anti-myeloma efficacy. We will (Aim 2) determine the effects of the potent osteoblast-activating factors, dickkopf-1 (DKK1) neutralizing antibody, parathyroid hormone (PTH) and bortezomib on myeloma bone disease and myeloma development and progression in primary myelomatous SCID-rab mice. We will (Aim 3) determine the role of FAP in myeloma pathogenesis and as a potential microenvironment-targeted therapy; using recombinant FAP, specific FAP inhibitors and short-interfering RNA approaches we will unravel direct and indirect effects of FAP on myeloma progression in vitro and in vivo. Work under this study will validate novel microenvironmental-targeted therapies associated with activation of osteoclasts and explore the use of bone-anabolic agents and SLRPs as effective and safe strategies to improve patients' quality of life and control myeloma. Project Narrative: Malignant myeloma cells manifest in the bone marrow and cause severe, painful bone disease. Our main goal is to create a hostile environment for tumor cells by controlling myeloma-induced bone destruction. Our study will increase knowledge of myeloma pathogenesis, which will help develop new approaches to treat myeloma bone disease and tumor progression simultaneously, improve patients' quality of life, and prevent myeloma development in individuals who are at risk for developing this incurable disease.