The career development activities outlined in this K23 proposal will provide didactic and experiential training under a mentored experience in several areas new to Dr. Sung Choi. She will acquire biostatistical skills and knowledge in specific areas of clinical research, learn new laboratory techniques, and develop ethical principles and research integrity essential for the conduct of human subject research. Thus, the comprehensive curriculum will complement her existing skills with new and advanced techniques and approaches with the goal of developing an independent, patient-oriented research career as a translational investigator in the field of bone marrow transplantation (BMT). With support of the K23, Dr. Choi will conduct a mentored patient-oriented research project in alignment with her training activities and overall career goals. Allogeneic BMT is a potentially curative therapy for many non-hematologic and hematologic diseases. Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic BMT and prevents this curative therapy from wider application. Current pharmacologic agents for GVHD prevention and treatment primarily target an essential effector for GVHD, donor T cells. Other key effectors for GVHD, and therefore potential therapeutic targets, are antigen presenting cells (APCs). Therefore, agents that target the allostimulatory functions of APCs may be an innovative therapeutic potential in the GVH process. Histone deacetylase (HDAC) inhibitors are novel anti-tumor agents that appear to be well-tolerated in human clinical trials. However, their immunomodulatory effects have thus far been largely unrecognized. Pre-clinical data generated in the laboratory of Dr. Reddy, Dr. Choi's mentor, form the rationale for this proposal. Dr. Choi will test the central hypothesis that HDAC inhibition will reduce the severity of GVHD by suppressing the functions of human APCs, the key mediators of GVHD, in an innovative Phase II clinical trial. These studies could allow for the development of a novel class of immunomodulatory drugs for attenuating GVHD.
The specific aims of the clinical trial are: 1) To conduct a Phase II trial using vorinostat in addition to standard immunosuppression to prevent GVHD in related donor reduced intensity conditioning (RIC) BMT. 2) To determine the cellular and plasma markers of deacetylase inhibition on inflammation after vorinostat administration following related donor RIC BMT. In summary, this K23 will provide Dr. Choi with the time and resources to: 1) execute a novel clinical trial and perform robust correlative studies within a well-defined mentoring structure;2) obtain formal training in clinical research design and statistical analyses;3) increase her research productivity;4) develop skills in manuscript and grant preparation;and 5) evolve into an independent investigator. Allogeneic bone marrow transplantation is a potentially curative therapy for many malignant and nonmalignant conditions whose applicability has been impeded by the development of its most serious complication, graft-versus-host disease (GVHD). A novel preventive strategy to mitigate GVHD will allow for better harnessing of this effective therapeutic modality.

Public Health Relevance

Allogeneic bone marrow transplantation is a potentially curative therapy for many malignant and nonmalignant conditions whose applicability has been impeded by the development of its most serious complication, graft-versus-host disease (GVHD). A novel preventive strategy to mitigate GVHD will allow for better harnessing of this effective therapeutic modality.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI091623-04
Application #
8591176
Study Section
Special Emphasis Panel (ZAI1-QV-I (S1))
Program Officer
Prograis, Lawrence J
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
$132,300
Indirect Cost
$9,800
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chang, Lawrence; Frame, David; Braun, Thomas et al. (2014) Engraftment syndrome after allogeneic hematopoietic cell transplantation predicts poor outcomes. Biol Blood Marrow Transplant 20:1407-17
Keusch, Florian; Rao, Rohini; Chang, Lawrence et al. (2014) Participation in clinical research: perspectives of adult patients and parents of pediatric patients undergoing hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 20:1604-11
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
Gatza, Erin; Braun, Thomas; Levine, John E et al. (2014) Etanercept plus topical corticosteroids as initial therapy for grade one acute graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 20:1426-34
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
Hanauer, David A; Zheng, Kai; Commiskey, Elaine L et al. (2013) Computerized prescriber order entry implementation in a physician assistant-managed hematology and oncology inpatient service: effects on workflow and task switching. J Oncol Pract 9:e103-14
Choi, Sung; Hoffmann, Sandra; Cooling, Laura (2012) Another case of acute cardiopulmonary toxicity with cord blood infusion: is dextran the culprit? Transfusion 52:207-8
Choi, Sung; Reddy, Pavan (2011) Donor Tregs suppress the good with the bad after allogeneic BMT. Leuk Res 35:1541-2