Inhibition of PGE2 for mobilization of autologous peripheral blood stem cells

抑制 PGE2 对自体外周血干细胞动员的影响

• 批准号: 8633799
• 负责人: Sherif S Farag
• 金额: $ 34.95万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633799
• 关键词: Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Autologous; Autologous Stem Cell Transplantation; B-Lymphocytes; Biological; Blood; Blood Component Removal; Blood Platelets; Bone Marrow; CD34 gene; CSF3 gene; CXCR4 gene; Cells; Clinical; Collecting Cell; Collection; Correlative Study; Data; Dendritic Cells; Dinoprostone; Disadvantaged; Disease; Disease remission; Dose; Economics; Engraftment; Enzymes; Filgrastim; Future; Gene Chips; Genes; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; High Dose Chemotherapy; Immune; Mediating; Modality; Molecular; Multiple Myeloma; Myelogenous; Natural Killer Cells; Nature; Non-Hodgkin' s Lymphoma; Ontology; Pathway interactions; Patients; Peripheral Blood Stem Cell; Pharmaceutical Preparations; Phase II Clinical Trials; Platelet Count measurement; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteasome Inhibitor; Publications; Recovery; Regimen; Relapse; Reporting; Resources; Role; Safety; Source; Stem cells; T-Lymphocyte Subsets; Time; Translating; Transplantation; United States Food and Drug Administration; chemotherapy; cost; cost effective; improved; interest; large cell Diffuse non-Hodgkin' s lymphoma; meloxicam; neutrophil; novel; peripheral blood; pre-clinical; public health relevance; small molecule; success; trafficking

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.

项目描述