The major objective of this Mentored Clinical Scientist Development Award (K08) proposal is the development of the candidate's academic career in the field of leukemia biology and stem cell transplantation. The candidate proposes in this application to learn new skills in genome analysis and mass spectrometry in order to complete a novel research investigation to discover leukemia stem cell-associated minor histocompatibility antigens. Since moving to the University of North Carolina in 2009, the candidate has been funded by a UNC Department of Medicine KL2 Award to develop bioinformatic and immunologic methods for minor histocompatibility antigen discovery. In this K08 proposal, the candidate has identified Dr. Chuck Perou, PhD, as his primary mentor and advisor in the application of RNA sequencing analysis aimed at the computational predication of leukemia stem cell associated minor histocompatibility antigens (LSC-associated mHA). Dr. Perou is a leader in the field of cancer genomics, and the leader of the UNC contribution to The Cancer Genome Atlas. He has mentored many graduate and post-doctoral students and has developed a comprehensive training and mentorship plan for the candidate so that he can develop new skills in genome analysis. The candidate has also identified Dr. Gary Glish PhD as a co-mentor to provide training and mentorship in mass spectrometry. The candidate has a PhD in Chemistry, but has no specific formal training in mass spectrometry. Because mass spectrometry plays a crucial role in antigen discovery research the candidate is proposing training and research in this field as part of the overall K08 project. Dr. Glish is a professor of Chemistry at UNC and the Past President of the American Society of Mass Spectrometry. He has mentored numerous graduate students through his very successful career, and will provide training in the theory and practice of mass spectrometry in the detection of biomolecules. Additionally, Dr. Glish's laboratory has developed and built a prototype high-field asymmetric waveform ion mobility spectrometry (FAIMS) mass spectrometer that will be used for the first time to probe for specifically predicted peptides in a biological sample. In addition to the mentorship provided by Dr. Perou and Dr. Glish, the candidate will receive advice and recommendations from an advisory panel consisting of Dr. Jon Serody and Dr. D. Neil Hayes in human T cell immunology and computational biology. The candidate's research will closely follow his mentorship plan as he will use his training in genomics and computational biology to predict LSC-associated mHA, and then confirm their production in leukemia using HPLC-FAIMS mass spectrometry. The long-term goal of this project is to predict and confirm common, immunogenic, LSC-associated mHA, as described in this K08 proposal, and to then develop them as targets for LSC-directed immune therapy. From the research conducted in this proposal, the training, mentorship and academic research infrastructure provided through UNC and its Lineberger Comprehensive Cancer Center the candidate will be able to successfully transition to become in independent NID-funded investigator.

Public Health Relevance

Allogeneic stem cell transplantation (SCT) is the standard of care therapy for eligible patients with high-risk acute myeloid leukemia (AML). While this treatment can cure up to 40% of patients with high-risk AML who undergo SCT while in complete remission overall survival in this patient group is dramatically reduced because of disease relapse and complications from graft vs. host disease. One way to improve overall survival in these patients is to develop novel immune therapies that specifically target the leukemia stem cell without targeting other organs. This research proposal describes a novel method aimed at predicting and confirming leukemia stem cell-associated minor histocompatibility antigens that can be developed into targeted immune therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL113594-03
Application #
8617862
Study Section
Special Emphasis Panel (ZHL1-CSR-K (F1))
Program Officer
Welniak, Lisbeth A
Project Start
2012-05-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$132,088
Indirect Cost
$9,784
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Dharmasiri, Udara; Isenberg, Samantha L; Glish, Gary L et al. (2014) Differential ion mobility spectrometry coupled to tandem mass spectrometry enables targeted leukemia antigen detection. J Proteome Res 13:4356-62
Kovarik, Michelle L; Shah, Pavak K; Armistead, Paul M et al. (2013) Microfluidic chemical cytometry of peptide degradation in single drug-treated acute myeloid leukemia cells. Anal Chem 85:4991-7
Zhang, Mao; Sukhumalchandra, Pariya; Enyenihi, Atim A et al. (2013) A novel HLA-A*0201 restricted peptide derived from cathepsin G is an effective immunotherapeutic target in acute myeloid leukemia. Clin Cancer Res 19:247-57
Wood, W A; Whitley, J; Goyal, R et al. (2013) Effectiveness of etoposide chemomobilization in lymphoma patients undergoing auto-SCT. Bone Marrow Transplant 48:771-6