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Kinase Targeting Therapies in Chronic Lymphocytic Leukemia: Mechanisms of Acquired Ibrutinib Resistance and the Pre-Clinical Development of OSU-T315

Liu, Ta-Ming
http://rave.ohiolink.edu/etdc/view?acc_num=osu1404917090

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in western countries. Despite the improvement of treatment that is contributed by development of targeted therapy through antibodies and chemical agents to unique surface markers or critical kinases triggering survival signals in CLL, satisfactory remission remains deficient and requires improvement for this incurable disease. Given improved understanding of the etiology and prognosis in CLL biology, the development of therapeutic approaches shifts to targeting critical molecules relied on by CLL cells. Of note, B cell receptor (BCR) and phosphoinositide-3 kinase (PI3K)/AKT both appear to be the central axis triggering survival signals in this malignancy, and the majority of agents in clinical use suppress these pathways by focusing on inhibiting proximal kinases such as bruton’s tyrosine kinase (BTK) and p110 δ subunits of PI3 Kinase, respectively. Nowadays, the best characterized first-in class agent inhibiting BTK and showing outstanding activities in CLL therapy is Ibrutinib. Despite the outstanding activity, no agent received as a monotherapy can achieve a complete remission; while relapse still occurs in patients receiving ibrutinib treatment, there is justification for developing new therapies. The work presented herein focuses on two main projects, the identification of genetic lesions related to Ibrutinib resistance, and the evaluation of OSU-T315 as a CLL therapeutic. Chapter 1 begins with introductions of B cell and CLL biology, comprising diagnostic and therapeutic strategies in this disease. The key survival signaling triggered by diverse kinases within the tumor environment will be outlined. Chapter 2 discusses the discovery of genetic lesions associated with Ibrutinib resistance. Using high-throughput sequencing, we uncover acquired genetic mutations in BTK, the direct target of Ibrutinib, or in the immediate downstream molecule of BTK, phospholipase C γ 2 (PLC γ 2), which drives CLL survival by antagonizing the therapeutic effect of Ibrutinib, leading to refractory disease. Functional studies show the mutations in BTK reverse inhibition of kinase activity, while gain-of function mutations in PLC γ 2 propagate downstream survival signals such as AKT and extracellular signal-related kinase (ERK) after bypassing BTK inhibition by Ibrutinib. In chapter 3, we report a novel agent OSU-T315, originally designed by targeting the scaffold of the AKT docking site in integrin-linked kinase (ILK), represents better selectivity toward CLL cells compared to the alleviated cytotoxicity in normal B or T lymphocytes. In contrast to current kinase inhibitors targeting proximal molecules, OSU-T315 diminishes AKT phosphorylation by displacing AKT translocation into lipid rafts, representing a unique strategy targeting the PI3K/AKT cascade. Further characterization reveals OSU-T315 abrogates both intrinsic and extrinsic stimuli-mediated survival signals, including BCR, CD40, toll-like receptor 9 (TLR9) and CD49d, accompanied by the reduced level of anti-apoptotic molecules myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-xl), thus leading to caspase-dependent apoptosis. The in vivo efficacy is supported by improved median survival in T cell leukemia/lymphoma 1 (TCL1) leukemia-engrafted mice. Pharmacology of this agent showed acceptable properties for eventual transition to clinical development, although further modification to improve bioavailabilty and formulation may be required. Chapter 4 concludes our findings with perspective implications. Particularly, the chapter addresses the unanswered questions and proposes future directions. Together, the work here provides first, novel mechanisms illustrating the genetic mutations associated with resistance in Ibrutinib therapy that may be relevant to further development for BCR signaling inhibitors; second, we also identify OSU-T315 as a PI3K/AKT signaling blocker and apply the strategy in the lipid raft compartment for CLL and other related diseases.
John Byrd, MD (Advisor)
Amy Johnson, PhD (Advisor)
Ching-Shih Chen, PhD (Committee Member)
Gregory Lesinski, PhD (Committee Member)
152 p.
Biomedical Research
Ibrutinib resistance, OSU-T315

Recommended Citations

Citations

  • Liu, T.-M. (2014). Kinase Targeting Therapies in Chronic Lymphocytic Leukemia: Mechanisms of Acquired Ibrutinib Resistance and the Pre-Clinical Development of OSU-T315 [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1404917090

    APA Style (7th edition)

  • Liu, Ta-Ming. Kinase Targeting Therapies in Chronic Lymphocytic Leukemia: Mechanisms of Acquired Ibrutinib Resistance and the Pre-Clinical Development of OSU-T315. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1404917090.

    MLA Style (8th edition)

  • Liu, Ta-Ming. "Kinase Targeting Therapies in Chronic Lymphocytic Leukemia: Mechanisms of Acquired Ibrutinib Resistance and the Pre-Clinical Development of OSU-T315." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1404917090

    Chicago Manual of Style (17th edition)

osu1404917090
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This open access ETD is published by The Ohio State University and OhioLINK.