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Targeting Protein Phosphatase 2a as a Therapeutic Strategy for Chronic Lymphocytic Leukemia

Liu, Qing
http://rave.ohiolink.edu/etdc/view?acc_num=osu1213301219

Abstract Details

2008, Doctor of Philosophy, Ohio State University, Pharmacy.
Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the western world. Despite significant progress in recent years, most patients eventually develop resistance to currently available therapies and succumb to the disease. New and more efficacious therapeutic agents with novel molecular targets are urgently needed. Protein phosphatase 2A (PP2A) is an emerging target for cancer therapy. It dephosphorylates various substrates and controls many signaling pathways that are related to cell survival or apoptosis. Therapies that target PP2A have promising activities against a variety of malignancies. FTY720, an activator of PP2A and lenalidomide, a negative regulator of PP2A, therefore, constitute the main subjects of this dissertation. In the first part of this research, FTY720, an immunosuppressant that is currently in phase III clinical trial for renal transplantation and multiple sclerosis, was investigated as a novel therapy for CLL. FTY720 was reported to induce immunosuppression as an antagonist of sphingosine-1-phosphate (S1P) receptors. Furthermore, it was found to activate PP2A in a human T cell line. In our studies, FTY720 was shown to mediate cell death in primary CLL B cells and B cell lines with a mechanism that is S1P receptor independent and PP2A activation dependent. FTY720 demonstrated significant therapeutic efficacy in a SCID mouse Raji xenograft model. This drug warrants further investigation as a therapeutic for clinical management of CLL and other B-cell lymphoproliferative disorders. In the second part of the dissertation, FTY720 was evaluated in mantle cell lymphoma (MCL), which like CLL, is a B-cell malignancy. FTY720 was shown to down regulate two key signaling proteins, Cyclin D1 and Akt, which are implicated in the pathogenesis of MCL, and to exhibit therapeutic activity in an animal model. In the third part of the research, lenalidomide, an immunomodulatory agent that is currently in clinical use for multiple myeloma and 5q-myelodysplastic syndrome (MDS), was studied for its effects on CLL B cells. Lenalidomide has previously been shown to induce partial and complete remissions in CLL patients while concurrently causing tumor flare reaction (TFR) in some patients. To facilitate pharmacokinetic/pharmacodynamic studies in future clinical trials requiring low levels of lenalidomide, a highly sensitive method for analyzing tissue and plasma concentrations of this agent by liquid chromatography/mass spectrometry was developed. This method was validated according to the guidelines provided by the FDA. Furthermore, using this analytical method, it was found that lenalidomide was unstable under standard culture conditions, which leads to the adoption of a revised dosing schedule for further in vitro studies on lenalidomide. In summary, research carried out as part of this dissertation advanced our understanding of the mechanisms of FTY720 and lenalidomide as potential therapeutic agents for CLL and provided support for further pre-clinical studies and clinical evaluation of these promising drugs in CLL and other B-cell malignancies.
John Byrd (Committee Chair)
James Dalton (Committee Co-Chair)
Raj Muthusamy (Committee Member)
William Hayton (Committee Member)
Pharmaceuticals
FTY720; Lenalidomide; chronic lymphocytic leukemia; mantle cell lymphoma; PP2A

Recommended Citations

Citations

  • Liu, Q. (2008). Targeting Protein Phosphatase 2a as a Therapeutic Strategy for Chronic Lymphocytic Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1213301219

    APA Style (7th edition)

  • Liu, Qing. Targeting Protein Phosphatase 2a as a Therapeutic Strategy for Chronic Lymphocytic Leukemia. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1213301219.

    MLA Style (8th edition)

  • Liu, Qing. "Targeting Protein Phosphatase 2a as a Therapeutic Strategy for Chronic Lymphocytic Leukemia." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1213301219

    Chicago Manual of Style (17th edition)

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© 2008, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.