Inhibition of PGE2 for mobilization of autologous peripheral blood stem cells

项目描述 动员的自体外周血干细胞（PBSC）已取代骨髓作为造血干细胞的来源。 造血干细胞因为更快的中性粒细胞和血小板的恢复，主要是由于更高的产量 PBSC移植物中CD 34+细胞的数量。使用骨髓生长因子，特别是G-CSF的各种动员策略 （非格司亭）已经单独使用或与化疗联合使用。然而，高达40%的患者 将不能动员“最佳”CD 34细胞剂量（定义为e5 × 106/kg）。普乐沙福，一种小分子CXCR 4 拮抗剂，与G-CSF组合，已显示增加动员的总CD 34+细胞， G-CSF单独使用，并且被食品和药物管理局批准用于患有以下疾病的患者的PBSC动员： 多发性骨髓瘤（MM）和非霍奇金淋巴瘤（NHL）。然而，普乐沙福的一个显著缺点是， 在最近的一项经济分析中，与NHL患者单独使用G-CSF相比，每位患者增加了25，567美元。 此外，14-24%接受普乐沙福+G-CSF治疗的MM和NHL患者仍未能采集e2 x106 在大型试验中，单采4天的CD 34+细胞/kg。我们的团队长期以来一直对以下角色感兴趣： 前列腺素E2（PGE 2）和环氧合酶（考克斯）通路对造血和HSC及HPC的影响 我们最近定义了PGE 2在造血生态位中的新作用，并表明非PGE 2在造血生态位中的作用。 抑制负责PGE 2合成的考克斯酶的甾体抗炎药（NSAID 显著增加外周血中HSC和HPC的数量，并与G-CSF协同作用， 动员具有上级移植潜力的PBSC。该提案旨在将我们的临床前发现转化为 开发一种新的、廉价的和更有效的PBSC动员方案。具体而言，我们建议： 1开展II期临床试验，评估美洛昔康与 非格司亭用于动员MM和NHL患者的自体PBSC，假设联合 FDA批准的NSAID、美洛昔康和非格司亭将增加NHL中收集的CD 34+细胞的数量 和接受ASCT的MM患者，目的2利用分子、表型和功能方法， 更好地了解NSAID对PBSC移植物含量和功能的作用机制，评估 动员移植物的CD 34+细胞及其CXCR 4的表达、增殖状态和免疫细胞 内容（Aim 2A），并进行基因表达微阵列和基因本体富集分析， CD 34+细胞/HPC亚群，以鉴定与NSAID介导的 HPC增殖潜力（目的2B）。从长远来看，了解这些变化将使我们能够更多地 有效地弥合移植后的分化差距，并开发新的和潜在的更有效的 以及具有成本效益的动员办法和战略。

PROJECT DESCRIPTION Mobilized autologous peripheral blood stem cells (PBSC) have replaced bone marrow as the source of hematopoietic stem cells because of more rapid neutrophil and platelet recovery, largely due to a higher yield of CD34+ cells in PBSC grafts. Various mobilization strategies using myeloid growth factors, particularly G-CSF (filgrastim), have been used either alone or in combination with chemotherapy. However, up to 40% of patients will fail to mobilize an "optimal" CD34 cell dose (defined as e5x106/kg). Plerixafor, a small molecule CXCR4 antagonist, in combination with G-CSF has been shown to increase total CD34+ cells mobilized compared to G-CSF alone, and is approved by the Food and Drug Administration for PBSC mobilization in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). However, a significant disadvantage of plerixafor is cost, adding $25,567 per patient compared to G-CSF alone in NHL patients in a recent economic analysis. Furthermore, 14-24% of MM and NHL patients receiving plerixafor plus G-CSF still failed to collect e2x106 CD34+ cells/kg in four days of apheresis in large trials. Our group has a long standing interest in the roles of prostaglandin E2 (PGE2) and the cyclooxygenase (COX) pathway on hematopoiesis and HSC and HPC trafficking, We have recently defined a new role for PGE2 in the hematopoietic niche and shown that non- steroidal anti-inflammatory drugs (NSAID) that inhibit COX enzymes responsible for PGE2 synthesis significantly enhance the number of HSC and HPC in peripheral blood, and act synergistically with G-CSF to mobilize PBSC with superior engraftment potential. This proposal seeks to translate our preclinical findings to develop a novel, inexpensive and more efficacious PBSC mobilizing regimen. Specifically, we propose to: Aim 1 Conduct a phase II clinical trial to assess the safety and efficacy of the combination of meloxicam and filgrastim for mobilizing autologous PBSC in patients with MM and NHL, hypothesizing that the combination of the FDA approved NSAID, meloxicam, and filgrastim will enhance the number of CD34+ cells collected in NHL and MM patients undergoing ASCT, and Aim 2 Utilize a molecular, phenotypic and functional approach to better understand the mechanism of action of NSAID on PBSC graft content and function, assessing the mobilized graft for CD34+ cells and their expression of CXCR4, and proliferation status, and immune cell content (Aim 2A), and performing gene expression microarrays and gene ontology enrichment analysis on CD34+ cells/HPC subsets to identify genes/biological pathways associated with NSAID-mediated change in HPC proliferative potential (Aim 2B). In the long-term, understanding these changes will allow us to more effectively bridge the differentiation gap post-transplant, and develop novel and potentially more efficacious and cost-effective mobilization regimens and strategies.