Targeting Myeloma Cell-Host Bone Marrow Interactions

在上一个资助期，我们专注于确定骨髓（BM）微环境在多发性骨髓瘤（MM）细胞生长，存活和耐药性中的作用。重要的是，我们已经成功地将多个新的药物（硼替佐米，来那度胺）靶向这些相互作用从实验室到床边和FDA批准用于治疗MM。我们以前的研究集中在BM环境的细胞成分，包括成纤维细胞，破骨细胞，成骨细胞和内皮细胞。在这个更新的申请中，我们将重点描述浆细胞样树突状细胞（pDC）的作用，主要是 我们的数据表明，pDC在MM中功能失调，因为它们不刺激T细胞应答。重要的是，即使在常规和新型药物存在下，它们也能诱导MM细胞生长和存活。因此，目前的建议试图提高我们对MM细胞与pDC的细胞间相互作用及其治疗相关性的理解，并具体解决三个相互关联的假设：1）MM细胞的生物学行为受到它们与pDC的相互作用的调节; 2）pDC-MM相互作用的分子和功能后遗症代表潜在的治疗靶点;和3）这些相互作用在体内的聚集相互作用允许合理设计新的单一和组合靶向疗法。基于这些假设，本提案侧重于一套不同但相互作用和互补的方法。具体目标。我们建议：表征pDC在体外MM细胞生长、存活、耐药性和迁移中的作用（具体目标1）;确定介导pDC-MM相互作用的分子和细胞机制，并验证其功能意义和治疗相关性（具体目标2）;并使用MM动物模型验证靶向介导pDC-MM体内相互作用的分子和细胞机制的新型疗法，用于I/II期评价。II临床试验（具体目标3）。总体而言，这些研究将为MM的新治疗策略中直接靶向pDC或阻断pDC-MM相互作用提供基础，以增强MM细胞毒性，克服耐药性并改善患者结局。

In the previous funding period, we focused on identifying the role of the bone marrow (BM) microenvironment in conferring growth, survival, and drug resistance in multiple myeloma (MM) cells. Importantly, we have successfully translated multiple novel agents (bortezomib, lenalidomide) targeting these interactions from the bench to the bedside and FDA approval for treatment of MM. Our prior studies have focused on the cellular components of BM milieu including fibroblasts, osteoclasts, osteoblasts, and endothelial cells. In this renewal application, we will focus on characterizing the role of plasmacytoid dendritic cells (pDCs), predominantly localized in the MM BM, in the pathophysiology of MM. Our data show that pDCs are dysfunctional in MM, since they do not stimulate T cell responses. Importantly, they induce MM cell growth and survival even in the presence of conventional and novel drugs. The current proposal therefore attempts to enhance our understanding of the intercellular interaction of MM cells with pDCs and its therapeutic relevance, and specifically addresses three inter-related hypotheses: 1) the biological behavior of MM cells is modulated by their interactions with pDCs; 2) the molecular and functional sequelae of pDC-MM interactions represent potential therapeutic targets; and 3) the aggregate interplay of these interactions in vivo allows for the rational design of novel single and combination targeted therapies. Based on these hypotheses, the current proposal focuses on a set of distinct, yet mutually interacting and complementary. Specific Aims. We propose: to characterize the role of pDCs in MM cell growth, survival, drug resistance and migration in vitro (Specific Aim 1); to identify the molecular and cellular mechanisms mediating pDC-MM interactions and validate their functional significance and therapeutic relevance (Specific Aim 2); and to validate novel therapies targeting molecular and cellular mechanisms mediating pDC-MM interactions in vivo using MM animal models for evaluation in phase-I/II clinical trials (Specific Aim 3). Overall, these studies will provide the basis for either directly targeting pDCs or blocking the pDC-MM interaction in novel therapeutic strategies for MM to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.