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Zach Hing Dissertation 4-4-18.pdf (2.12 MB)

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Targeting Nuclear Export in Chronic Lymphocytic Leukemia

Hing, Zachary Andrew
http://rave.ohiolink.edu/etdc/view?acc_num=osu1523543484958313

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
In the past decade there has been increased appreciation for the complexity and importance of post-transcriptional processes that control gene regulation and post-translational processes that control protein function in the cell. In particular, intense study has focused on how they become altered in cancer. Nuclear transport controls both of these processes through temporospatial separation of macromolecules. Alterations of nuclear export, particularly via dysregulation of the exportin 1/chromosome region maintenance 1 (XPO1/CRM1) pathway, have recently been identified in many different human cancers, including chronic lymphocytic leukemia (CLL), where XPO1 inactivates tumor suppressor and cell cycle regulatory proteins by sequestering them from the nucleus. In CLL, recent therapies targeting components of the B cell receptor pathway such as inhibitors to Bruton tyrosine kinase (BTK) have produced dramatic response rates; however, complete responses are infrequent and resistance to BTK inhibition is a growing clinical concern. Therefore, restoring nuclear localization of tumor suppressor proteins via inhibition of XPO1 is a promising strategy to reestablishing their function. Oral selective inhibitor of nuclear export (SINE) compounds block XPO1 function and represent a novel therapeutic approach in CLL. The lead SINE compound, selinexor, has shown promise in clinical trials, but is limited to twice weekly dosing. Therefore, novel SINE compounds with enhanced tolerability may result in improved clinical efficacy. In addition, we hypothesized that combination of XPO1 blockade with BTK inhibition may result in increased efficacy. Herein we describe the discovery and characterization of a novel SINE compound and the identification of novel targeted combination therapies using dual XPO1 and BTK inhibition. Using a combination of cell-free, in vitro, and in vivo models we have established the efficacy of a novel XPO1 inhibitor, KPT-8602. The identification of rational drug combinations in oncology holds promise as a strategy to increase durability of responses and prevent resistance to any single-agent. In CLL, combination strategies that display synergy with ibrutinib are of intense interest to address the growing issue of acquired drug resistance. Rational combination strategies that include XPO1 blockade are particular appealing as a method of restoring function to multiple tumor suppressor proteins and eliciting synergistic responses. Here, we have described a novel combination therapy targeting XPO1 and BTK that results in synergistic responses in CLL. We also demonstrate that XPO1 inhibition is active in the growing setting of acquired ibrutinib resistance. Overall, our data indicate that nuclear export represents a promising therapeutic target in CLL, particularly in the setting of acquired resistance to ibrutinib. Moreover, combination therapies that encompass XPO1 inhibition hold promise in CLL. These results may have relevance to other cancers in which XPO1 overexpression is seen.
John Byrd, MD (Advisor)
Rosa Lapalombella, PhD (Advisor)
Robert Baiocchi, MD PhD (Committee Member)
Lynne Abruzzo, MD PhD (Committee Member)
Guramrit Singh, PhD (Committee Member)
123 p.
Biomedical Research
Leukemia; B-cell; targeted therapies; nuclear export

Recommended Citations

Citations

  • Hing, Z. A. (2018). Targeting Nuclear Export in Chronic Lymphocytic Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523543484958313

    APA Style (7th edition)

  • Hing, Zachary. Targeting Nuclear Export in Chronic Lymphocytic Leukemia. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1523543484958313.

    MLA Style (8th edition)

  • Hing, Zachary. "Targeting Nuclear Export in Chronic Lymphocytic Leukemia." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523543484958313

    Chicago Manual of Style (17th edition)

osu1523543484958313
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This open access ETD is published by The Ohio State University and OhioLINK.