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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Pennsylvania State University
United States
Zip Code
Shaw, Jeremy; Costa-Pinheiro, Pedro; Patterson, Logan et al. (2018) Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era. Adv Cancer Res 140:327-366
Zhang, Xuewei; Kitatani, Kazuyuki; Toyoshima, Masafumi et al. (2018) Ceramide Nanoliposomes as a MLKL-Dependent, Necroptosis-Inducing, Chemotherapeutic Reagent in Ovarian Cancer. Mol Cancer Ther 17:50-59
Tan, Su-Fern; Pearson, Jennifer M; Feith, David J et al. (2017) The emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia. Expert Opin Ther Targets 21:583-590
Verma, Mohit K; Clemens, Julia; Burzenski, Lisa et al. (2017) A novel hemolytic complement-sufficient NSG mouse model supports studies of complement-mediated antitumor activity in vivo. J Immunol Methods 446:47-53
Olson, Kristine C; Kulling, Paige M; Olson, Thomas L et al. (2017) Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia. Cancer Biol Ther 18:290-303
Hengst, Jeremy A; Dick, Taryn E; Sharma, Arati et al. (2017) SKI-178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models. Cancer Transl Med 3:109-121
Morad, Samy A F; Davis, Traci S; MacDougall, Matthew R et al. (2017) Role of P-glycoprotein inhibitors in ceramide-based therapeutics for treatment of cancer. Biochem Pharmacol 130:21-33
Doshi, Ushma A; Shaw, Jeremy; Fox, Todd E et al. (2017) STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia. Signal Transduct Target Ther 2:17051
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
Tan, Su-Fern; Liu, Xin; Fox, Todd E et al. (2016) Acid ceramidase is upregulated in AML and represents a novel therapeutic target. Oncotarget 7:83208-83222

Showing the most recent 10 out of 27 publications