The Program's broad long-term objective is to develop new targeted therapeutics for acute myelogenous leukemia (AML). The overarching hypothesis of the Program Project is that sphingolipid metabolism is altered in AML and can be used to direct therapeutic regimens. A corollary of this hypothesis suggests that novel therapeutics that target dysfunctional sphingolipid metabolism may be highly efficacious in AML. The integration of the Program follows the metabolism of ceramide. Project 1 targets ceramide metabolism utilizing ceramide-based nanotherapeutics;Projects 2 and 3 target acid ceramidase and sphingosine kinase, which coordinately generate the pro-mitogenic and anti-apoptotic ceramide metabolite, sphingosine- 1-phosphate, and Project 4 targets P-glycoprotein-mediated glycosylation of ceramide. All Projects have validated therapeutic modalities in both in vitro and in vivo models of AML. The Program is supported by five integral Cores. These include the: Synthesis and Nanoformulation Core, which provides synthesized compounds not available commercially for biologic studies;Targeted Sphing""""""""omics"""""""" Core, which is essential for quantification of sphingolipid metabolism;Animal Modeling and Clinical Resources Core, which provides state-of-the-art molecularly defined AML samples with annotated clinical outcomes and murine leukemia stem cells models;Biostatistics Core, which provides critical research design and analysis;Administrative Core, which provides oversight and coordination of all scientific, administrative, and fiscal activities. Development of targeted therapeutics for AML will be pursued in the following overall Specific Aims of the Program: 1. Engineer, characterize and optimize novel lipomimetic- or small molecule-based therapeutics for AML. 2. Validate the efficacy and toxicology of sphingolipid-targeted therapeutics in vivo using murine leukemia stem cells models. 3. Define the role of altered sphingolipid metabolism in cell survival, apoptosis, autophagy, and drug resistance in AML. To accomplish these Aims, we have assembled a transdisciplinary team of clinical and basic scientists, organic chemists, and material scientists. We are fortunate that NCI NanoCharacterization Laboratory has accelerated pre-clinical development of the Penn State ceramide liposomal nanoplatform. The clinical significance of the Program rests on the urgent and unmet needs for development of new therapeutics in AML. In the revised application, we have specifically responded to all of the reviewer's critiques, in particular, addressing the major issues associated with AML heterogeneity and humanized AML murine models. Importantly, we have documented engraftment in NSG mice of AML subsets defined by integrated genetic profiling.

Public Health Relevance

Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. Unfortunately, 75% of patients who initially respond to conventional chemotherapy develop drug-resistant relapse. New therapeutics for AML are urgently needed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA171983-02
Application #
8732613
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Arya, Suresh
Project Start
2013-09-10
Project End
2018-08-31
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
Pharmacology
Type
Schools of Medicine
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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