A major theme of this leukemia SPORE application is translational research that focuses on identifying therapeufically relevant targets for anti-leukemic drug discovery. Each of the projects presented in this application is a testament to a strong collaborative effort between clinicians and basic scientists, which nterfaces many aspects of translational research, including oncogenic signaling, epigenefics, experimental therapeufics, and immunology. The Medicinal Chemistry Core integrates the expertise of two laboratories, including medicinal chemistry, molecular and cell biology, and molecular pharmacology (Chen), and computational chemistry and structural biology (Li). In the past few years, this program has developed a series of agents targeting different molecular defects clinically relevant to leukemogenesis, two of which are ready to enter clinical trials in 2009. Thus, this core provides a platform to translate basic science findings from each of these projects into the design and synthesis of small-molecule agents for tesfing individual hypotheses, and adds an important dimension to expedite the translation from bench to the clinic. Specifically, the following three aims constitute the foci of this Medicinal Chemistry Core with initial emphasis on targefing immunomodulafion in tumor-specific T cells and natural killer cells (Project 3), and protein phosphatase (PP) 2A (Pilot Project 2), which will be expanded to address other new molecular targets arising from other projects. Overall, our specific aims include:
Aim 1. To carry out lead opfimizafion of lenalidomidie to develop specific immunomodulatory drugs for chronic lymphocytic leukemia (CLL) therapy (in collaboration with Project 3).
Aim 2. To carry out structural opfimization of FTY720 to develop novel PP2A-activating agents (in collaboration with Pilot Project 2).
Aim 3. To provide aspects of medicinal chemistry service including custom synthesis, sample preparafions, computational chemistry, and structural biology to interested investigators of this SPORE application (all Projects) and other NCI SPORE and POl investigators. An example of this is providing OSU-HDAC42 to investigators in Projects 4, 5 and Developmental Project 1. Overall, this unique core will provide members of the SPORE a greater opportunity to translate findings into therapeutic opfions for patients with leukemia.

Public Health Relevance

This Core provides support in synthetic medicinal chemistry and structural biology/computational chemistry to individual projects to translate basic science findings into the design and synthesis of small-molecule agents for hypothesis testing. Lead compounds with therapeutic potential will further undergo structural optimization to develop potent agents for clinical translafion.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA140158-04
Application #
8380674
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$132,996
Indirect Cost
$63,889
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Walker, C J; Eisfeld, A-K; Genutis, L K et al. (2017) No evidence for microsatellite instability in acute myeloid leukemia. Leukemia 31:1474-1476
Sekeres, Mikkael A; Othus, Megan; List, Alan F et al. (2017) Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol 35:2745-2753
Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2017) Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality. Cancer Res 77:207-218
Park, I-K; Blum, W; Baker, S D et al. (2017) E3 ubiquitin ligase Cbl-b activates the p53 pathway by targeting Siva1, a negative regulator of ARF, in FLT3 inhibitor-resistant acute myeloid leukemia. Leukemia 31:502-505
Papaioannou, Dimitrios; Shen, Changxian; Nicolet, Deedra et al. (2017) Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia. Proc Natl Acad Sci U S A 114:E4641-E4647
Eisfeld, A-K; Kohlschmidt, J; Schwind, S et al. (2017) Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia. Leukemia 31:1278-1285
Papaioannou, Dimitrios; Nicolet, Deedra; Volinia, Stefano et al. (2017) Prognostic and biologic significance of long non-coding RNA profiling in younger adults with cytogenetically normal acute myeloid leukemia. Haematologica 102:1391-1400
Wiczer, Tracy E; Levine, Lauren B; Brumbaugh, Jessica et al. (2017) Cumulative incidence, risk factors, and management of atrial fibrillation in patients receiving ibrutinib. Blood Adv 1:1739-1748
Miller, Cecelia R; Ruppert, Amy S; Heerema, Nyla A et al. (2017) Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib. Blood Adv 1:1584-1588
Mani, R; Yan, R; Mo, X et al. (2017) Non-immunosuppressive FTY720-derivative OSU-2S mediates reactive oxygen species-mediated cytotoxicity in canine B-cell lymphoma. Vet Comp Oncol 15:1115-1118

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