New treatments are needed for graft-vs-host disease (GVHD), the most serious complication of allogeneic bone marrow transplantation (BMT). Current pharmacologic agents for GVHD prevention and treatment primarily target one of the essential effectors for GVHD, donor T cells. Other key effectors for GVHD, and therefore potential therapeutic targets, are antigen presenting cells (APCs). Extensive experimental data developed by this PPG support the conduct of translational clinical trials to test agents that act upon this additional GVHD mechanism. We have demonstrated that APC function can be modulated by histone deacetylase inhibitors (HDACi) and in preliminary data we published, that the HDACi, suberoylanalide hydroxamic acid (SAHA), also known as vorinostat, regulates experimental GVHD. In this project will perform a unique clinical trial of this drug for GVHD prevention. A further advance in GVHD, the individualization of treatment, is presently hampered because GVHD can not be predicted precisely, the diagnosis is often hard to establish, and patients whose GVHD is likely to be resistant to standard therapy can not be identified. One of the first GVHD biomarker panels with predictive and diagnostic power was identified in work supported by this projecL We have recently identified multiple additional biomarkers using a large-scale proteomics discovery approach. In this project we will integrate newly discovered biomarkers with those already validated to create informative and clinically useful panels for allogeneic BMT patients.
The Specific Aims are: 1. To conduct a Phase II trial using the HDACi, vorinostat in addition to standard immunosuppression to prevent GVHD in related donor reduced intensity transplantation 2. To develop biomarkers specific to GVHD target organs (skin and Gl tract). 3. To validate eight newly discovered candidate proteins as biomarkers for the diagnosis, prognosis and prediction of systemic acute GVHD. 4. To optimize predictive, diagnostic, and prognostic biomarker panels using validated combinations of target organ specific and systemic biomarkers and to analyze their value in new clinical trials.

Public Health Relevance

Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant diseases whose applicability has been impeded by the development of its most serious complication, GVHD. Strategies that mitigate GVHD will allow for better harnessing of this effective therapeutic modality to treat many patients with hematological cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-J)
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University of Michigan Ann Arbor
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Glick, Gary D; Rossignol, Rodrigue; Lyssiotis, Costas A et al. (2014) Anaplerotic metabolism of alloreactive T cells provides a metabolic approach to treat graft-versus-host disease. J Pharmacol Exp Ther 351:298-307
Choi, Sung Won; Braun, Thomas; Chang, Lawrence et al. (2014) Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol 15:87-95
Vander Lugt, Mark T; Braun, Thomas M; Hanash, Samir et al. (2013) ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med 369:529-39
Harris, Andrew C; Ferrara, James L M; Levine, John E (2013) Advances in predicting acute GVHD. Br J Haematol 160:288-302
MacDonald, Kelli P; Shlomchik, Warren D; Reddy, Pavan (2013) Biology of graft-versus-host responses: recent insights. Biol Blood Marrow Transplant 19:S10-4
Byersdorfer, Craig A; Tkachev, Victor; Opipari, Anthony W et al. (2013) Effector T cells require fatty acid metabolism during murine graft-versus-host disease. Blood 122:3230-7
Levine, John E; Huber, Elisabeth; Hammer, Suntrea T G et al. (2013) Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortality. Blood 122:1505-9
Harris, Andrew C; Kitko, Carrie L; Couriel, Daniel R et al. (2013) Extramedullary relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcomes. Haematologica 98:179-84
Brown, J R; Kim, H T; Armand, P et al. (2013) Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome. Leukemia 27:362-9
Paczesny, Sophie (2013) Discovery and validation of graft-versus-host disease biomarkers. Blood 121:585-94

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