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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA039542-26
Application #
8545541
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
26
Fiscal Year
2013
Total Cost
$259,935
Indirect Cost
$87,438
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Levine, John E; Braun, Thomas M; Harris, Andrew C et al. (2015) A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol 2:e21-9
Tkachev, Victor; Goodell, Stefanie; Opipari, Anthony W et al. (2015) Programmed death-1 controls T cell survival by regulating oxidative metabolism. J Immunol 194:5789-800
Levine, John E; Hogan, William J; Harris, Andrew C et al. (2014) Improved accuracy of acute graft-versus-host disease staging among multiple centers. Best Pract Res Clin Haematol 27:283-7

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