This career development proposal is designed to provide training and support for the applicant to become an independent translational researcher focused on the biology and treatment of acute myeloid leukemia (AML). The goals of this proposal are to 1. To obtain didactic training in clinical research design, methodology for interpreting results of clinical research studies. 2. To develop clinical expertise in the treatment of AML and other hematologic malignancies. 3. To develop the """"""""survival skills"""""""" necessary in clinical research including grant and manuscript writing, public speaking, navigating regulatory issues, and promoting effective collaborations. In AML, interaction of leukemic blasts with the bone marrow microenvironment may protect against spontaneous apoptosis and genotoxic stresses such as chemotherapy. The long term goal of this project is to identify and test therapies which target the protective effect of the marrow microenvironment. We hypothesize that by disrupting leukemia stromal interactions we will sensitize AML to the effects of cytotoxic chemotherapy. Although many candidate receptor-ligand pairs have been implicated, CXCR4 (expressed on normal and leukemic stem cells), and its ligand SDF-1 (expressed on BM stromal cells and osteoblasts) play a central role in stem cell homing and retention in the BM. We will test the ability of AMD3100, a small molecule inhibitor of CXCR4, to chemosensitize AML in a clinical trial entitled, """"""""A phase l/ll study of AMD3100 plus mitoxantrone, etoposide, and cytarabine (AMD3100-I-MEC) in relapsed or refractory AML."""""""" We predict that like normal HSCs, AMD3100 will mobilize leukemic blasts in patients with AML. We will perform correlative studies to examine AML mobilization and alterations in CXCR4 / SDF-1 signaling in response to AMD3100. We will also continue to identify and test alternative pathways which mediate leukemia stromal interactions.

Public Health Relevance

The goal of this proposal is to train an independent physician-scientist for a career as a translational researcher focused on the development of novel therapies for acute myeloid leukemia (AML). The proposed research plans to target the bone marrow microenvironment to improve the effectiveness of treatment of AML.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Uy, G L; Duncavage, E J; Chang, G S et al. (2017) Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy. Leukemia 31:872-881
Uy, Geoffrey L; Mandrekar, Sumithra J; Laumann, Kristina et al. (2017) A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv 1:331-340
Uy, G L; Rettig, M P; Stone, R M et al. (2017) A phase 1/2 study of chemosensitization with plerixafor plus G-CSF in relapsed or refractory acute myeloid leukemia. Blood Cancer J 7:e542
Al-Hussaini, Muneera; Rettig, Michael P; Ritchey, Julie K et al. (2016) Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. Blood 127:122-31
Uy, Geoffrey L; Hsu, Yen-Michael S; Schmidt, Amy P et al. (2015) Targeting bone marrow lymphoid niches in acute lymphoblastic leukemia. Leuk Res 39:1437-42
Goyal, S D; Zhang, M-J; Wang, H-L et al. (2015) Allogeneic hematopoietic cell transplant for AML: no impact of pre-transplant extramedullary disease on outcome. Bone Marrow Transplant 50:1057-62
Rashidi, Armin; Uy, Geoffrey L (2015) Targeting the microenvironment in acute myeloid leukemia. Curr Hematol Malig Rep 10:126-31
Morris, Gerald P; Uy, Geoffrey L; Donermeyer, David et al. (2013) Dual receptor T cells mediate pathologic alloreactivity in patients with acute graft-versus-host disease. Sci Transl Med 5:188ra74
Uy, Geoffrey L; Rettig, Michael P; Motabi, Ibraheem H et al. (2012) A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 119:3917-24
Wang, Tzu-Fei; Klein, Jonathan L; Woodard, Pamela K et al. (2012) Plasmacytoma-like post-transplantation lymphoproliferative disease occurring in a cardiac allograft: a case report and review of the literature. J Clin Oncol 30:e278-82

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