The Synthesis and Nanoformulation Core (SNC) will supply ceramide analogs, acid ceramidase (AC) inhibitors, sphingosine kinase inhibitors, and tamoxifen metabolites essential to the members of this Program Project. In addition, the Core will also provide liposomal formulations of C6-ceramide derivatives, acid ceramidase inhibitors, sphingosine kinase inhibitor SKI-178, and tamoxifen metabolites to the Projects 1, 2, 3, and 4, respectively. Furthermore, the Core will also synthesize [3H] AC inhibitors and [14C] SKI-178 for Projects 2 and 3. The purpose of the SNC is to advance the productivity of various Projects by developing and providing the above referred classes of chemical agents that are not commercially available, for biological investigations to be conducted by scientists belonging to all four Projects. The scientists working in the SNC are highly experienced in developing efficient synthetic routes for drug-like small molecules. The research activities of the SNC encompass the development of syntheses of desired agents. The structural integrity and purity of all agents will be ensured by state-of-the-science technology, including HPLC, TLC, UV, MS, LCMS and NMR.
The specific aims to accomplish the objectives of this Core are: (1) Synthesize required acid ceramidase inhibitors, ceramide analogs, sphingosine kinase inhibitors, and tamoxifen analogs for biological studies proposed in the Program. The class of compounds to be synthesized for each Project is listed in Table 1;(2) Synthesize radiolabeled acid ceramidase inhibitor LCL 204 and sphingosine kinase inhibitor SKI-178 to be used for ADME studies in Projects 2 and 3, respectively; (3) Encapsulate the novel Ce-ceramide analogs, acid ceramidase and sphingosine kinase inhibitors, and tamoxifen analogs into nanoliposomal formulations.

Public Health Relevance

A successful completion of this Program Project, that is focused on defining the biological basis of dysfunctional sphingolipid metabolism in AML and new therapeutic targets for molecular and lipidomimetic treatment approaches, requires novel chemical agents. Since the syntheses techniques are beyond the scope and experience of individual Project leaders, the inclusion of SNC in this proposal is highly relevant.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA171983-02
Application #
8757117
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
DUNS #
City
Hershey
State
PA
Country
United States
Zip Code
17033
Najima, Yuho; Tomizawa-Murasawa, Mariko; Saito, Yoriko et al. (2016) Induction of WT1-specific human CD8+ T cells from human HSCs in HLA class I Tg NOD/SCID/IL2rgKO mice. Blood 127:722-34
Morad, Samy A F; Ryan, Terence E; Neufer, P Darrell et al. (2016) Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia. J Lipid Res 57:1231-42
Young, Megan M; Takahashi, Yoshinori; Fox, Todd E et al. (2016) Sphingosine Kinase 1 Cooperates with Autophagy to Maintain Endocytic Membrane Trafficking. Cell Rep 17:1532-1545
Linton, Samuel S; Sherwood, Samantha G; Drews, Kelly C et al. (2016) Targeting cancer cells in the tumor microenvironment: opportunities and challenges in combinatorial nanomedicine. Wiley Interdiscip Rev Nanomed Nanobiotechnol 8:208-22
Olson, Kristine C; Kulling, Paige M; Olson, Thomas L et al. (2016) Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL Leukemia. Cancer Biol Ther :0
Liu, Qiang; Chen, Longgui; Atkinson, Jennifer M et al. (2016) Atg5-dependent autophagy contributes to the development of acute myeloid leukemia in an MLL-AF9-driven mouse model. Cell Death Dis 7:e2361
Aoki, Yuki; Watanabe, Takashi; Saito, Yoriko et al. (2015) Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia. Blood 125:967-80
Hasanali, Zainul S; Saroya, Bikramajit Singh; Stuart, August et al. (2015) Epigenetic therapy overcomes treatment resistance in T cell prolymphocytic leukemia. Sci Transl Med 7:293ra102
Morad, Samy A F; Cabot, Myles C (2015) Tamoxifen regulation of sphingolipid metabolism--Therapeutic implications. Biochim Biophys Acta 1851:1134-45
Kester, Mark; Bassler, Jocelyn; Fox, Todd E et al. (2015) Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic. Biol Chem 396:737-47

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