Myeloma-Microenvironment Interaction Dynamics

描述（由申请人提供）：骨髓瘤的特征是恶性浆细胞在骨髓中积聚，并伴有严重的骨骼疾病。 在美国，每年有超过14，000人患有骨髓瘤;尽管治疗取得了进展，但骨髓瘤仍然无法治愈，这突出了为这种疾病开发新干预措施的重要性。我们证明了骨髓瘤骨疾病和肿瘤进展之间的相互依赖性。 因此，我们提出了一种创新的治疗模式，其基础是通过刺激骨形成、增加抗肿瘤成骨细胞因子和阻断促进骨髓瘤的成骨细胞因子的活性来为骨髓瘤创造一个不适宜生存的骨髓环境。 这一治疗概念得到了临床观察和我们先前和初步研究的支持，这些研究表明，成骨细胞抑制骨髓瘤生长，成骨细胞活化剂诱导骨形成，同时也降低了体内骨髓瘤负荷。 此外，成骨细胞产生高水平的富含小亮氨酸的蛋白聚糖（SLRP），这是必要的适当的骨重建，值得注意的是，也抑制一些肿瘤类型;我们的初步研究表明，SLRP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生长，我们确定成纤维细胞活化因子（FAP）是参与这一过程的关键微环境因子。 我们的总体假设是，骨髓瘤骨中破骨细胞上调的因子促进骨髓瘤细胞存活，成骨细胞产生的骨生成因子抑制骨髓瘤进展。 我们将利用我们独特的原发性骨髓瘤体内和体外系统来研究三个特定目标。 我们将（目的1）确定SLRP参与成骨细胞诱导的骨髓瘤生长抑制，并解开这些蛋白聚糖体外和体内抗骨髓瘤的分子机制。 我们将测试阻断SLRP对成骨细胞诱导的骨髓瘤生长抑制的影响，阐明SLRP的分子机制，并测试其抗骨髓瘤疗效。 我们将（目的2）确定有效的成骨细胞活化因子，dickkopf-1（DKK 1）中和抗体，甲状旁腺激素（PTH）和硼替佐米对骨髓瘤骨病和骨髓瘤的发展和进展的影响，在原发性骨髓瘤SCID-rab小鼠。 我们将（目的3）确定FAP在骨髓瘤发病机制中的作用，并作为一种潜在的微环境靶向治疗;使用重组FAP，特异性FAP抑制剂和短干扰RNA方法，我们将在体外和体内阐明FAP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活化相关的新型微环境靶向疗法，并探索使用骨合成代谢药物和SLRP作为有效和安全的策略，以改善患者的生活质量和控制骨髓瘤。 项目叙述：恶性骨髓瘤细胞在骨髓中出现，并导致严重的疼痛性骨病。 我们的主要目标是通过控制骨髓瘤引起的骨破坏来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，这将有助于开发新的方法来同时治疗骨髓瘤骨病和肿瘤进展，改善患者的生活质量，并预防有发展这种不治之症风险的个体的骨髓瘤发展。

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.