Human acute myelogenous leukemia (AML) is highly heterogeneous and, as demonstrated by this group, exhibits significant variability in sphingoiipid metabolism. Current therapy of AML is highly toxic, yielding ultimately inadequate outcomes for the vast majority of patients. Cell lines are limited in their representation of primary AML subtypes and manifest clonal evolution in culture, suggesting limitations in their relationship to the primary case material. The systematic study of these diseases thus requires access to primary samples representing a substantial pool of cases, and correlation of these samples to clinical data including treatment outcomes. Animal models of various kinds are available, but models representing direct leukemogenesis via expression of relevant oncogenic proteins and immunodeficient xenografts propagating primary AML, provide relevant platforms for studying developing therapies. In this Core, materials and models will be provided to each Project to allow completion of proposed objectives. The following specific aims will be pursued:
Specific Aim 1 : Expand and maintain the PSHCI leukemia cell bank to provide programmatic access to cell and plasma samples from a broad variety of AML patients and normal hematopoietic controls. Samples will be cryopreserved in multiple aliquots to allow repeated interrogation via developing technologies. Clinical data will be collected and available to provide biologically meaningful categorization of AMLs.
Specific Aim 2 : Develop and maintain a menu of animal models in which to test promising program-derived therapies. Two such models are available.
Sub aim 2 A: Xenograft models of primary human leukemia have been developed in N0D/SCID/IL2ry (NSG) murine hosts and used as platforms for testing novel therapies. Multiple lines (originating from multiple AMLs of differing subtypes) will be passaged in NSG animals to provide in vivo validation of therapeutics. Human cord blood will be expanded in NSG mice to provide normal controls for in vivo toxicity studies.
Sub aim 2 B: Murine syngeneic models of AML using retroviral transduction of murine bone marrow cells with fusion protein oncogenes. We have established a MLL-AF9 retroviral transduction model, which develops a stem cell derived leukemia shown to be inhibited by Project-derived therapeutics. This Core is essential to the overall Program, each project of which uses primary, cells and in vivo models as provided here. These materials and testing platforms will allow development of novel therapies for these lethal diseases.

Public Health Relevance

The overall goals of the present project are to study sphingoiipid metabolism in AML, and to design novel sphingolipid-based therapeutics for the treatment of AML. This Core will serve an essential role for all projects by maintaining a repository of human AML samples with defined clinical outcomes, as well as by developing robust murine models to test the efficacy of the project's sphingolipid-based AML therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA171983-02
Application #
8757119
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
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
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
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
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
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

Showing the most recent 10 out of 27 publications