Inhibition of PGE2 for mobilization of autologous peripheral blood stem cells

项目说明 动员的自体外周血干细胞(PBSC)已取代骨髓成为干细胞的来源 造血干细胞，因为中性粒细胞和血小板恢复得更快，主要是由于产量更高 CD34+细胞在PBSC移植物中的表达。使用髓系生长因子，特别是G-CSF的各种动员策略 (非格列西姆)，已单独使用或与化疗联合使用。然而，多达40%的患者 将无法动员“最佳”CD34细胞剂量(定义为e5x106/kg)。小分子CXCR4--plerixafor 拮抗剂与G-CSF联合使用可增加CD34+细胞的动员总量 G-CSF单独使用，并被食品和药物管理局批准用于慢性粒细胞白血病患者的PBSC动员 多发性骨髓瘤(MM)和非霍奇金淋巴瘤(NHL)。然而，plerixafor的一个显著缺点是 是成本，在最近的一项经济分析中，与NHL患者仅使用G-CSF相比，每个患者增加了25,567美元。 此外，接受普利沙福加G-CSF治疗的14-24%的MM和NHL患者仍然无法收集e2x106 在大型试验中，CD34+细胞/公斤在四天的采集期。我们集团长期以来一直对以下角色感兴趣 前列腺素E_2(PGE_2)和环氧合酶(COX)途径与造血和HSC、HPC的关系 贩运，我们最近定义了PGE2在造血利基中的新角色，并表明非 抑制负责PGE2合成的COX酶的类固醇抗炎药(NSAID) 显著增加外周血中HSC和HPC的数量，并与G-CSF协同作用 动员具有良好植入潜力的PBSC。这项提案旨在将我们的临床前发现转化为 开发一种新颖、廉价、更有效的PBSC动员方案。具体地说，我们建议： 1进行II期临床试验，以评估美洛昔康和美洛昔康联合应用的安全性和有效性 非格列辛用于动员MM和NHL患者的自体PBSC，假设 FDA批准的非甾体抗炎药、美洛昔康和非格列西汀将增加在NHL中收集的CD34+细胞的数量 和接受ASCT的MM患者，以及AIM 2利用分子、表型和功能方法 更好地了解非甾体抗炎药对PBSC移植物含量和功能的作用机制，评估 CD34+细胞的动员移植物及其CXCR4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化分析 CD34+细胞/HPC亚群用于识别与非甾体抗炎药介导的血管内皮细胞病变相关的基因/生物通路 HPC增殖潜能(目标2B)。从长远来看，了解这些变化将使我们能够 有效地弥合移植后的分化差距，开发出新的和潜在更有效的 以及具有成本效益的动员方案和战略。

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.