Targeting Protein Metabolism in B-cell Malignancies
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The Ohio State University / OhioLINK
2012
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=osu1343169973 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu13431699732021-08-03T06:06:02Z Targeting Protein Metabolism in B-cell Malignancies Gupta, Sneha Veeraraghavan CLL Protein Metabolism Carfilzomib Silvestrol acute lymphoblastic leukemia chronic lymphocytic leukemia 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. 2012-08-16 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1343169973 http://rave.ohiolink.edu/etdc/view?acc_num=osu1343169973 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
CLL Protein Metabolism Carfilzomib Silvestrol acute lymphoblastic leukemia chronic lymphocytic leukemia |
| spellingShingle |
CLL Protein Metabolism Carfilzomib Silvestrol acute lymphoblastic leukemia chronic lymphocytic leukemia Gupta, Sneha Veeraraghavan Targeting Protein Metabolism in B-cell Malignancies |
| author |
Gupta, Sneha Veeraraghavan |
| author_facet |
Gupta, Sneha Veeraraghavan |
| author_sort |
Gupta, Sneha Veeraraghavan |
| title |
Targeting Protein Metabolism in B-cell Malignancies |
| title_short |
Targeting Protein Metabolism in B-cell Malignancies |
| title_full |
Targeting Protein Metabolism in B-cell Malignancies |
| title_fullStr |
Targeting Protein Metabolism in B-cell Malignancies |
| title_full_unstemmed |
Targeting Protein Metabolism in B-cell Malignancies |
| title_sort |
targeting protein metabolism in b-cell malignancies |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2012 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1343169973 |
| work_keys_str_mv |
AT guptasnehaveeraraghavan targetingproteinmetabolisminbcellmalignancies |
| _version_ |
1719430889473048576 |