Inhibition of PGE2 for mobilization of autologous peripheral blood stem cells

Project: Research project

Description

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.
StatusFinished
Effective start/end date5/1/144/30/19

Funding

  • National Institutes of Health: $321,933.00
  • National Institutes of Health: $349,482.00
  • National Institutes of Health: $325,817.00

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Dinoprostone
Granulocyte Colony-Stimulating Factor
meloxicam
Non-Hodgkin's Lymphoma
Anti-Inflammatory Agents
Multiple Myeloma
Transplants
Prostaglandin-Endoperoxide Synthases
Pharmaceutical Preparations
Hematopoietic Stem Cell Mobilization
Costs and Cost Analysis
Phase II Clinical Trials
Gene Ontology
Blood Component Removal
Hematopoiesis
United States Food and Drug Administration
Peripheral Blood Stem Cells
Combination Drug Therapy
Intercellular Signaling Peptides and Proteins
Neutrophils

ASJC

  • Medicine(all)