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You searched for +publisher:"The Ohio State University" +contributor:("Johnson, Amy"). Showing records 1 – 2 of 2 total matches.

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The Ohio State University

1. Liu, Ta-Ming. Kinase Targeting Therapies in Chronic Lymphocytic Leukemia: Mechanisms of Acquired Ibrutinib Resistance and the Pre-Clinical Development of OSU-T315.

Degree: PhD, Molecular, Cellular and Developmental Biology, 2014, The Ohio State University

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 d 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 ¿ 2 (PLC ¿ 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 ¿ 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… Advisors/Committee Members: Byrd, John (Advisor), Johnson, Amy (Advisor).

Subjects/Keywords: Biomedical Research; Ibrutinib resistance, OSU-T315

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APA (6th Edition):

Liu, T. (2014). Kinase Targeting Therapies in Chronic Lymphocytic Leukemia: Mechanisms of Acquired Ibrutinib Resistance and the Pre-Clinical Development of OSU-T315. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1404917090

Chicago Manual of Style (16th 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. Doctoral Dissertation, The Ohio State University. Accessed June 16, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1404917090.

MLA Handbook (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. Web. 16 Jun 2019.

Vancouver:

Liu T. Kinase Targeting Therapies in Chronic Lymphocytic Leukemia: Mechanisms of Acquired Ibrutinib Resistance and the Pre-Clinical Development of OSU-T315. [Internet] [Doctoral dissertation]. The Ohio State University; 2014. [cited 2019 Jun 16]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1404917090.

Council of Science Editors:

Liu T. Kinase Targeting Therapies in Chronic Lymphocytic Leukemia: Mechanisms of Acquired Ibrutinib Resistance and the Pre-Clinical Development of OSU-T315. [Doctoral Dissertation]. The Ohio State University; 2014. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1404917090


The Ohio State University

2. Rozewski, Darlene M. Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice.

Degree: PhD, Pharmacy, 2012, The Ohio State University

Lenalidomide and pomalidomide belong to a novel class of immunomodulatory (IMiD) drugs and have anti-angiogenic, anti-inflammatory, pro-erythropoietic and further anti-cancer activities. Both agents have shown promising therapeutic efficacy in multiple clinical applications, and lenalidomide has been approved by the United States Food and Drug Administration for use in multiple myeloma and myelodysplastic syndrome. Although many therapeutic activities have been discovered, the exact mechanistic targets of these agents remain to be elucidated and the mechanisms responsible for adverse effects are unknown. Additionally, transporters responsible for IMiD disposition, absorbance and clearance have not yet been identified. The use of animals in this regard may prove beneficial. However, pharmacokinetic evaluations necessary for these studies are absent from the literature. Herein, we (1) validate a method for lenalidomide quantification in murine plasma and tissues and verify application of the method to those of dosed mice, (2) perform a full comprehensive pharmacokinetic evaluation of lenalidomide in mice to classify dose linearity, intraperitoneal and oral bioavailability, and tissue disposition following multiple intravenous doses, (3) perform a pharmacokinetic evaluation of pomalidomide in mice following intravenous and oral administration and provide evidence of IMiD transport through the ABC efflux transporter P-glycoprotein. Advisors/Committee Members: Phelps, Mitch (Committee Co-Chair), Johnson, Amy (Committee Co-Chair), Byrd, John (Advisor).

Subjects/Keywords: Pharmaceuticals; Lenalidomide; Pharmacokinetics; Mouse; P-glycoprotein; Disposition; Bioavailability; Transporter

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Rozewski, D. M. (2012). Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1331144282

Chicago Manual of Style (16th Edition):

Rozewski, Darlene M. “Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice.” 2012. Doctoral Dissertation, The Ohio State University. Accessed June 16, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1331144282.

MLA Handbook (7th Edition):

Rozewski, Darlene M. “Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice.” 2012. Web. 16 Jun 2019.

Vancouver:

Rozewski DM. Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice. [Internet] [Doctoral dissertation]. The Ohio State University; 2012. [cited 2019 Jun 16]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1331144282.

Council of Science Editors:

Rozewski DM. Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice. [Doctoral Dissertation]. The Ohio State University; 2012. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1331144282

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