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Targeting Protein Metabolism in B-cell Malignancies

Gupta, Sneha Veeraraghavan
http://rave.ohiolink.edu/etdc/view?acc_num=osu1343169973

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Pharmacy.
Protein metabolism comprises the biochemical processes that regulate the synthesis of proteins, their post-translational modification and degradation. In cancer cells, pathways targeting protein metabolism are often deregulated to accumulate signals that promote survival. These changes are manifested in malignant cells by way of upregulation of protein synthesis, suppression of protein degradation and selective expression of anti-apoptotic, pro-proliferative and pro-survival proteins. B-cell malignancies such as chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL) are caused by the accumulation of B cells that are resistant to apoptosis. Both diseases are characterized by imbalanced expression of pro-apoptotic and anti-apoptotic Bcl-2 family members, constitutive expression of the nuclear factor NF-κB and mutations or deletions in the tumor suppressor p53 - signals that support the survival of leukemic B cells. Current therapies in CLL and ALL target normal immune cells in addition to malignant cells, causing profound immune suppression with an accompanying risk of lethal secondary infections. Furthermore, a common problem with most therapies is that patients who initially responded favorably relapse over time. To a large extent, this occurs in patients with advanced diseases that have p53 mutations in B cells, which become resistant to therapies dependent on wild-type p53 function. A major focus of therapeutic development has therefore been the investigation of agents that have minimal effects on T cells and are cytotoxic to B cells independent of p53 or overexpression of anti-apoptotic Bcl-2 family proteins. Two such therapeutic agents: silvestrol, a translation initiation inhibitor, and carfilzomib, a proteasome inhibitor, are introduced for the treatments of ALL and CLL in this thesis. The work presented herein provides proof of concept that drugs that affect protein metabolism pathways can selectively and potently target B cells over T cells while at the same time work independently of p53. The ultimate significance of this work is not only to accelerate the clinical development of silvestrol and carfilzomib in B-cell malignancies, but also to highlight the benefit of targeting protein metabolism in cancer.
John Byrd (Advisor)
David Lucas (Advisor)
Mitch Phelps (Committee Member)
Kristy Ainslie (Committee Member)
171 p.
CLL; Protein Metabolism; Carfilzomib; Silvestrol; acute lymphoblastic leukemia; chronic lymphocytic leukemia;

Recommended Citations

Citations

  • Gupta, S. V. (2012). Targeting Protein Metabolism in B-cell Malignancies [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343169973

    APA Style (7th edition)

  • Gupta, Sneha. Targeting Protein Metabolism in B-cell Malignancies. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1343169973.

    MLA Style (8th edition)

  • Gupta, Sneha. "Targeting Protein Metabolism in B-cell Malignancies." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343169973

    Chicago Manual of Style (17th edition)

osu1343169973
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© 2012, some rights reserved.Creative Commons License Targeting Protein Metabolism in B-cell Malignancies by Sneha Veeraraghavan Gupta is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.