Hematopoietic cell transplantation (HCT) provides a potentially curative treatment for a wide variety of diseases. HCT, however, is complicated by high incidence of transplant-related mortality, graft failure and graft versus host disease (GvHD). The interaction of stromal derived factor-1 (SDF-1) with CXCR4 chemokine receptor plays an indispensable role in hematopoietic stem cell homing and engraftment. We hypothesize that blocking the SDF-1/CXCR4 interaction with a specific CXCR4 antagonist would selectively enhance donor cell reconstitution in allogeneic HCT. Plerixafor is a highly specific and reversible antagonist of CXCR4 and will be used in the current study. Our recent studies in a congeneic mouse transplant model demonstrated that post-transplant administration of plerixafor significantly improved animal survival and selectively enhanced donor cell engraftment. This selective enhancement of donor cell reconstitution results from combined effects of mobilization of residual recipient stem cells by plerixafor and selective survival advantage of donor stem cells. The objectives of this proposal are to perform pivotal translational studies to move our study into a phase I/II clinical trial at the end of this award and to further dissect the mechanisms of plerixafor and the regulation of CXCR4 signaling. We have 2 specific aims.
Our Aim 1 is to investigate the efficacy of plerixafor in enhancing donor cell engraftment in several allogeneic mouse transplant models that are directly relevant to clinical applications.
Our Aim 2 is to further dissect the mechanisms through which plerixafor enhances donor cell reconstitution and to understand the regulation of CXCR4 signaling. Successful accomplishment of these aims will have important implications in HCT and will benefit patients with HCT. Furthermore, our study will shed new lights into the role of CXCR4 in hematopoietic stem cell homing, mobilization and expansion, as well as the regulation of CXCR4 signaling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL103780-06
Application #
8882519
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Welniak, Lisbeth A
Project Start
2014-08-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Paul, Barry; Kang, Shuqi; Zheng, Zhihong et al. (2018) The challenges of checkpoint inhibition in the treatment of multiple myeloma. Cell Immunol 334:87-98
Zheng, Zhihong; Fan, Shengjun; Zheng, Jing et al. (2018) Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma. J Hematol Oncol 11:29
Sundaramoorthy, Pasupathi; Wang, Qinhong; Zheng, Zhihong et al. (2017) Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice. Stem Cell Res Ther 8:263
Green, Michael M B; Chao, Nelson; Chhabra, Saurabh et al. (2016) Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery. J Hematol Oncol 9:71
An, Ningfei; Kang, Yubin (2014) Thioredoxin and hematologic malignancies. Adv Cancer Res 122:245-79
Venkata, Jagadish Kummetha; An, Ningfei; Stuart, Robert et al. (2014) Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. Blood 124:1915-25
Roof, Logan; Coker, Woodrow J; Lazarchick, John et al. (2014) Senile transthyretin cardiac amyloidosis in patients with plasma cell dyscrasias: importance of cardiac biopsy for making the correct diagnosis. Aperito J Cell Mol Biol 1:
Coker, Woodrow J; Jeter, Ashley; Schade, Henning et al. (2013) Plasma cell disorders in HIV-infected patients: epidemiology and molecular mechanisms. Biomark Res 1:8
An, Ningfei; Kraft, Andrew S; Kang, Yubin (2013) Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice. J Hematol Oncol 6:12
An, Ningfei; Lin, Ying-Wei; Mahajan, Sandeep et al. (2013) Pim1 serine/threonine kinase regulates the number and functions of murine hematopoietic stem cells. Stem Cells 31:1202-12

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