Myeloma-Microenvironment Interaction Dynamics

描述（申请人提供）：骨髓瘤以骨髓内恶性浆细胞积聚为特征，伴有严重的骨病。在美国，每年有超过14000人患有骨髓瘤；尽管在治疗方面取得了进展，但骨髓瘤仍然无法治愈，这突出了开发新的干预措施对这种疾病的重要性。我们证明骨髓瘤骨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和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的骨髓环境。这一治疗理念得到了临床观察和我们之前和初步研究的支持，这些研究表明，成骨细胞抑制骨髓瘤的生长，成骨细胞激活剂诱导骨形成，同时也减少了骨髓瘤的体内负担。此外，成骨细胞产生高水平的富含小亮氨酸的蛋白聚糖（slrp），这是正确的骨重塑所必需的，值得注意的是，它也抑制某些肿瘤类型；我们的初步研究显示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的生长，并且我们确定成纤维细胞激活因子（FAP）是参与这一过程的关键微环境因素。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的存活，而成骨细胞产生的造骨因子抑制骨髓瘤的进展。我们将利用我们独特的体内和体外系统来研究原发性骨髓瘤的三个特定目标。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，并揭示这些蛋白聚糖在体内和体外的抗骨髓瘤分子机制。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，揭示slrp的分子机制，并测试其抗骨髓瘤的功效。我们将（目的2）确定强效成骨细胞激活因子、dickkopf-1 （DKK1）中和抗体、甲状旁腺激素（PTH）和硼替佐米对骨髓瘤骨病和原发性骨髓瘤scid - rabb小鼠骨髓瘤发生和进展的影响。我们将（目标3）确定FAP在骨髓瘤发病机制中的作用，并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，我们将在体外和体内揭示FAP对骨髓瘤进展的直接和间接影响。本研究将验证与破骨细胞激活相关的新型微环境靶向治疗，并探索骨合成代谢药物和slrp作为有效和安全的策略来改善患者的生活质量和控制骨髓瘤。

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.