Docosahexaenoate Oxidation in the Progression of Glioblastoma: Mechanistic Studies and Evaluation of a Therapeutic Antibody
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Case Western Reserve University School of Graduate Studies / OhioLINK
2019
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=case1544194949142565 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-case15441949491425652021-08-03T07:09:15Z Docosahexaenoate Oxidation in the Progression of Glioblastoma: Mechanistic Studies and Evaluation of a Therapeutic Antibody Tomko, Nicholas Daniel Chemistry Cellular Biology Biochemistry Medicine Oncology carboxyethylpyrrole 4-hydroxy-7-oxohept-5-enoic acid lactone CEP HOHA lactone oxidative stress docosahexaenoic acid angiogenesis bevacizumab glioblastoma GBM anti-CEP Matrix metalloproteases MMP1 cell migration GlioVis PAR1 Oxidative stress causes cleavage of docosahexaenoate (DHA), e.g., generating 4-hydroxy-7-oxohept-5-enoic acid lactone (HOHA lactone) that reacts with proteins to form 2-(ω-carboxyethyl)pyrrole (CEP) derivatives. Both HOHA lactone and CEP derivatives induce angiogenesis, a critical process that enables unrestrained growth of tumors. Avastin (bevacizumab), a monoclonal antibody that binds to vascular endothelial growth factor (VEGF), inhibits angiogenesis in cancers, e.g., the brain cancer glioblastoma (GBM). GBM patients have a significant decrease in the levels of DHA in the tumor compared to the surrounding tissue where DHA is the most abundant polyunsaturated fatty acyl. This suggested that DHA depletion by lipid peroxidation could be a prominent, but unexplored component in the pathogenesis of GBM. PET and MRI imaging techniques were developed to facilitate monitoring the response of the vasculature in vivo to anti-angiogenic therapeutics in subcutaneous and orthotopic xenografts. The growth inhibitory efficacy of an anti-CEP mouse monoclonal antibody was demonstrated in a subcutaneous model of GBM. The efficacy of anti-CEP is comparable to clinical doses of bevacizumab. Because angiogenesis signaling of the CEP and VEGF pathways are complementary and independent, we expected and confirmed that anti-CEP significantly retards progression tumors after failure of bevacizumab treatment. While CEP-induced angiogenesis involves migration and invasion of endothelial cells into the surrounding tissue, I found that CEP does not cause GBM stem cells to migrate.Matrix metalloproteases (MMPs) facilitate angiogenesis and cancer cell migration. In an analysis of clinical data, I discovered that increases in matrix metalloprotease-1 (MMP1) mRNA expression positively correlate with a poor prognosis and to an especially invasive GBM phenotype, and with three proteins indicative of oxidative stress: superoxide dismutase 2, NADPH oxidase 4, and carbonic anhydrase 9. I discovered that HOHA lactone causes increased expression of MMP1 by GBM stem cells and induces phosphorylation of mitogen-activated protein kinases and Akt kinase that is dependent on MMP1 and the protease-activated receptor 1 (PAR1). I discovered that HOHA lactone induces an increase in GBM stem cell migration velocity. The discoveries and the analytical techniques described in this thesis establish a foundation for investigating the pathological effects of lipid peroxidation in brain cancer. 2019-02-01 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1544194949142565 http://rave.ohiolink.edu/etdc/view?acc_num=case1544194949142565 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Chemistry Cellular Biology Biochemistry Medicine Oncology carboxyethylpyrrole 4-hydroxy-7-oxohept-5-enoic acid lactone CEP HOHA lactone oxidative stress docosahexaenoic acid angiogenesis bevacizumab glioblastoma GBM anti-CEP Matrix metalloproteases MMP1 cell migration GlioVis PAR1 |
| spellingShingle |
Chemistry Cellular Biology Biochemistry Medicine Oncology carboxyethylpyrrole 4-hydroxy-7-oxohept-5-enoic acid lactone CEP HOHA lactone oxidative stress docosahexaenoic acid angiogenesis bevacizumab glioblastoma GBM anti-CEP Matrix metalloproteases MMP1 cell migration GlioVis PAR1 Tomko, Nicholas Daniel Docosahexaenoate Oxidation in the Progression of Glioblastoma: Mechanistic Studies and Evaluation of a Therapeutic Antibody |
| author |
Tomko, Nicholas Daniel |
| author_facet |
Tomko, Nicholas Daniel |
| author_sort |
Tomko, Nicholas Daniel |
| title |
Docosahexaenoate Oxidation in the Progression of Glioblastoma: Mechanistic Studies and Evaluation of a Therapeutic Antibody |
| title_short |
Docosahexaenoate Oxidation in the Progression of Glioblastoma: Mechanistic Studies and Evaluation of a Therapeutic Antibody |
| title_full |
Docosahexaenoate Oxidation in the Progression of Glioblastoma: Mechanistic Studies and Evaluation of a Therapeutic Antibody |
| title_fullStr |
Docosahexaenoate Oxidation in the Progression of Glioblastoma: Mechanistic Studies and Evaluation of a Therapeutic Antibody |
| title_full_unstemmed |
Docosahexaenoate Oxidation in the Progression of Glioblastoma: Mechanistic Studies and Evaluation of a Therapeutic Antibody |
| title_sort |
docosahexaenoate oxidation in the progression of glioblastoma: mechanistic studies and evaluation of a therapeutic antibody |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2019 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1544194949142565 |
| work_keys_str_mv |
AT tomkonicholasdaniel docosahexaenoateoxidationintheprogressionofglioblastomamechanisticstudiesandevaluationofatherapeuticantibody |
| _version_ |
1719454760108556288 |