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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA140707-04
Application #
8277304
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
Project Start
2009-09-14
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$158,853
Indirect Cost
$11,693
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
Fehniger, Todd A; Uy, Geoffrey L; Trinkaus, Kathryn et al. (2011) A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia. Blood 117:1828-33
Uy, Geoffrey L; Lane, Andrew A; Welch, John S et al. (2010) A protease-resistant PML-RAR{alpha} has increased leukemogenic potential in a murine model of acute promyelocytic leukemia. Blood 116:3604-10