AML is a heterogeneous group of malignant disorders whose primary therapy has changed little in recent decades. Sphingolipid metabolism, centered on the pro-apoptotic molecule ceramide, represents an understudied therapeutic avenue in this and other malignancies. This project stems from the hypothesis that ceramide-based therapeutics can be utilized as selective and sensitive anti-cancer agents. Unfortunately, the potential of ceramide-based therapeutics is severely limited by cell-impermeability and hydrophobicity. We have pioneered the use of nanotechnology to turn ceramide from a hydrophobic agent into a hydrophilic drug, engineering a C6-ceramide nanoliposome with clear efficacy in cancer models. Preliminary data suggest that ceramide nanoliposomes are active in multiple AML cell lines and primary cases, but sensitivity is highly variable. Thus, the goal of the project is the design of second-generation ceramide nanoliposomes that exert efficacy in AML patients who are resistant to conventional chemotherapy.
In Specific Aim 1, we will optimize second-generation nanoliposomal ceramide therapy for the treatment of AML. To maximize efficacy, ceramide nanoliposomes will be re-engineered via encapsulation of pharmacological agents to inhibit ceramide metabolism or autophagy. We will also actively target ceramide nanoliposomes to AML progenitor populations, initially via conjugation of anti-CD117 (c-kit), which is preferentially expressed in hematopoitic stem cells.
In Specific Aim 2, we will investigate mechanisms underlying the enhanced efficacy between ceramide nanoliposomes and pharmacological agents that inhibit ceramide metabolism or autophagy. Specifically, based upon preliminary data, we will investigate if this synergism is mediated via a molecular-based switch from autophagy to apoptosis and/or a synergistic elevation of long chain pro-apoptotic ceramide species. We will also characterize the contribution of selective ceramide synthases to the elevation of long chain ceramide species in defined AML patient subtypes. With the indispensable support of programmatic projects and cores, this project will rapidly characterize and validate the efficacy of second-generation ceramide nanoliposomes in defined AML populations.
Acute myelogenous leukemia (AML) is biologically heterogeneous and exhibits significant variability in sphingolipid metabolism. Current therapy of AML is highly toxic and yields variable and ultimately inadequate outcomes. Additional therapeutic options are necessary for AML. The present project engineers, characterizes and validates second-generation ceramide nanoliposomes as selective and sensitive therapeutics in AML patients in poor prognostic categories. State of the art in-vivo models of AML blasts will allow assessment of ceramide-based therapeutics.
|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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