New strategies for targeted chronic myeloid leukemia therapy: disrupting BCR-ABL1 dimerization and secondary leukemia-specific pathways

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Title New strategies for targeted chronic myeloid leukemia therapy: disrupting BCR-ABL1 dimerization and secondary leukemia-specific pathways
Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Woessner, David W.
Date 2013-12
Description Chronic myeloid leukemia (CML) is identified by the unique reciprocal chromosomal translocation involving BCR and ABL1, the fusion of which generates a constitutively active tyrosine kinase. Of critical importance for kinase function is oligomerization of multiple BCR-ABL1 proteins, facilitated by the N-terminal coiled-coil (CC) domain in BCR. While antineoplastic therapies have historically been dominated by small molecule drugs with a broad impact on cancer, recently there has been a shift toward small molecule targeted therapeutics, which was led by the development of imatinib. Imatinib, a tyrosine kinase inhibitor (TKI), was rationally developed for the treatment of CML. Although imatinib has been extremely successful in disease modification and increasing overall survival, it, like many of the subsequently developed TKIs, is subject to failure when mutations in the BCR-ABL1 kinase domain (the target of TKIs) occur, or the cell loses its dependence on the BCR-ABL1 protein. We have broken from the small molecule development track and instead focused on peptide-based inhibition of the upstream oligomerization event in CML pathogenesis. We previously described the anticancer activity of a dimerization inhibitor derived from the CC domain, called CCmut2/3 (representing two different versions of coiled-coil inhibitors). Driven by the positive results in previous studies, we proposed the following overarching hypothesis: Differential manipulation of domains within one BCRABL1 protein; or parallel manipulation of multiple pathways within one iv BCR-ABL1-containing cell will lead to a potent therapy which may overcome TKIresistant disease. Here we examine this hypothesis to determine the efficacy of the CCmut2/3 for broad-spectrum CML disease. In one study we observed that use of the CCmut2 in concert with one of several selective leukemia-specific secondary pathway inhibitors enhances the apoptotic potential and limits the proliferative capacity of K562 BCR-ABL1-containing cells. Another study describes the broad anticancer inhibitory potential of CCmut3 in cells with varying mutational status in the BCR-ABL1 kinase domain. Finally we investigate the potential of CCmut3 in the context of human disease with a series of ex vivo inquires using patient samples. This dissertation focuses on demonstrating efficacy of CCmut2/3 as a front-line CML therapy against several cell lines including those with wild-type and mutant BCRABL1
Type Text
Publisher University of Utah
Subject MESH Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein-Tyrosine Kinases; Dimerization; Piperazines; Benzamides; Pyrimidines; Translocation, Genetic; Peptide Fragments; Multiprotein Complexes; Protein Kinase Inhibitors; Cell Line
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of New Strategies for Targeted Chronic Myeloid Leukemia Therapy: Disrupting BCR-ABL1 Dimerization and Secondary Leukemia-Specific Pathways. Spencer S. Eccles Health Sciences Library. Print version available at J. Willard Marriott Library Special Collections.
Rights Management Copyright © David W. Woessner 2013
Format application/pdf
Format Medium application/pdf
Format Extent 7,772,987 bytes
Source Original in Marriott Library Special Collections,
ARK ark:/87278/s6bs21cn
Setname ir_etd
ID 196620
Reference URL https://collections.lib.utah.edu/ark:/87278/s6bs21cn
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