The broad long term goal of this application is to design, develop and optimize the next-generation of pegylated C6-ceramide cationic liposomal formulations for treatment of large granular lymphocyte (LGL) leukemia. LGL leukemia arises from clonal proliferation of either T cells or natural killer (NK) cells. There is no known curative therapy for patients with LGL leukemia. Leukemic LGL are resistant to Fas-induced apoptosis and display high levels of activated STAT3, a critical mediator of oncogenic signaling. Inhibition of STAT3 in leukemic LGL causes a decrease in survival protein Mcl-1 and an increased sensitivity to Fas-mediated apoptosis. The foundation of this application is a first generation C6-ceramide nanoliposome which has been adopted as platform technology by the Nanotechnology Characterization Laboratory of the National Cancer Institute.
The specific aims are focused around the central hypothesis that nano-scale, non- aggregating C6-ceramide liposomes offer exquisitely sensitive, selective, non-toxic, stealthy, biodegradable and responsive platforms for systemically targeting hydrophobic chemotherapeutic drugs and/or siRNA to LGL leukemic cells. The potential clinical usefulness of multi-functional nanoliposomes, designed to deliver cell-permeable analogs of ceramide (C6 ceramide) as well as target-specific siRNA and/or Methotrexate, will be tested in a Fischer F344 rat model of LGL leukemia. It is hypothesized that simultaneous delivery of Methotrexate and/or siRNA in a ceramide-incorporated liposome will have synergistic efficacy in LGL leukemia. The first specific Aim will test the hypothesis that systemic delivery of liposomal short-chain ceramide inhibits LGL leukemia in an established animal model.
Specific Aim 2 will test the hypothesis that the pegylated cationic liposomes allow delivery of inhibitory siRNA and chemotherapeutic drugs into LGL leukemic cells in vitro and in vivo, such that their anti-leukemic activity is enhanced.
Specific Aim 3 will test the hypothesis that conjugation of a monoclonal antibody to CD8, the specific marker for LGL leukemia, will target the therapeutic liposomes to LGL leukemic cells in vitro and in vivo. Experiments in specific aim 3 are important proof-of-principle studies for delivery of immunoliposomes by targeting surface antigens expressed on cancer cells. Development of this second generation cancer nanotechnology platform as outlined in this application has potential for improved cancer therapeutics.
The goal of this application is to develop therapy for large granular lymphocyte (LGL) leukemia using a novel cancer nanotechnology platform. We propose to administer systemically targeted C6-ceramide cationic nanoimmunoliposome formulations encapsulating methotrexate and siRNAs to an established animal model of LGL leukemia. These studies will provide the foundation for utilizing this therapeutic approach in human subjects with this incurable disease.
|Loughran Jr, T P; Zickl, L; Olson, T L et al. (2015) Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia 29:886-94|
|Watters, Rebecca J; Fox, Todd E; Tan, Su-Fern et al. (2013) Targeting glucosylceramide synthase synergizes with C6-ceramide nanoliposomes to induce apoptosis in natural killer cell leukemia. Leuk Lymphoma 54:1288-96|
|Ryland, Lindsay K; Doshi, Ushma A; Shanmugavelandy, Sriram S et al. (2013) C6-ceramide nanoliposomes target the Warburg effect in chronic lymphocytic leukemia. PLoS One 8:e84648|
|Nyland, Susan Bell; Krissinger, Daniel J; Clemente, Michael J et al. (2012) Seroreactivity to LGL leukemia-specific epitopes in aplastic anemia, myelodysplastic syndrome and paroxysmal nocturnal hemoglobinuria: results of a bone marrow failure consortium study. Leuk Res 36:581-7|
|Leblanc, Francis; Zhang, Dan; Liu, Xin et al. (2012) Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets. Future Oncol 8:787-801|
|Liu, Xin; Loughran Jr, Thomas P (2011) The spectrum of large granular lymphocyte leukemia and Felty's syndrome. Curr Opin Hematol 18:254-9|
|Saadatpour, Assieh; Wang, Rui-Sheng; Liao, Aijun et al. (2011) Dynamical and structural analysis of a T cell survival network identifies novel candidate therapeutic targets for large granular lymphocyte leukemia. PLoS Comput Biol 7:e1002267|
|Lamy, Thierry; Loughran Jr, Thomas P (2011) How I treat LGL leukemia. Blood 117:2764-74|
|Watters, Rebecca J; Wang, Hong-Gang; Sung, Shen-Shu et al. (2011) Targeting sphingosine-1-phosphate receptors in cancer. Anticancer Agents Med Chem 11:810-7|
|Yu, Jianhua; Mitsui, Takeki; Wei, Min et al. (2011) NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human. J Clin Invest 121:1456-70|
Showing the most recent 10 out of 12 publications