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dc.contributor.advisorAlonzo Ross, PhD
dc.contributor.authorWeatherbee, Jessica L.
dc.date2022-08-11T08:08:46.000
dc.date.accessioned2022-08-23T16:07:24Z
dc.date.available2022-08-23T16:07:24Z
dc.date.issued2016-08-05
dc.date.submitted2016-11-23
dc.identifier.doi10.13028/M2V30X
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32240
dc.description.abstractGlioblastoma multiforme (GBM) is a deadly grade IV brain tumor characterized by a heterogeneous population of cells that are drug resistant, aggressive, and infiltrative. The current standard of care, which has not changed in over a decade, only provides GBM patients with 12-14 months survival post diagnosis. We asked if the addition of a novel endoplasmic reticulum (ER) stress inducing agent, JLK1486, to the standard chemotherapy, temozolomide (TMZ), which induces DNA double strand breaks (DSBs), would enhance TMZ’s efficacy. Because GBMs rely on the ER to mitigate their hypoxic environment and DNA repair to fix TMZ induced DSBs, we reasoned that DSBs occurring during heightened ER stress would be deleterious. Treatment of GBM cells with TMZ+JLK1486 decreased cell viability and increased cell death due to apoptosis. We found that TMZ+JLK1486 prolonged ER stress induction, as indicated by elevated ER stress marker BiP, ATF4, and CHOP, while sustaining activation of the DNA damage response pathway. This combination produced unresolved DNA DSBs due to RAD51 reduction, a key DNA repair factor. The combination of TMZ+JLK1486 is a potential novel therapeutic combination and suggests an inverse relationship between ER stress and DNA repair pathways.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectDissertations, UMMS
dc.subjectGlioblastoma
dc.subjectApoptosis
dc.subjectDNA Repair
dc.subjectEndoplasmic Reticulum
dc.subjectEndoplasmic Reticulum Stress
dc.subjectDNA Breaks, Double-Stranded
dc.subjectDNA Damage
dc.subjectDacarbazine
dc.subjectGlioblastoma
dc.subjectApoptosis
dc.subjectDNA Repair
dc.subjectEndoplasmic Reticulum
dc.subjectEndoplasmic Reticulum Stress
dc.subjectDouble-Stranded DNA Breaks
dc.subjectDNA Damage
dc.subjectDacarbazine
dc.subjectCancer Biology
dc.subjectCellular and Molecular Physiology
dc.subjectNeoplasms
dc.titleExploiting DNA Repair and ER Stress Response Pathways to Induce Apoptosis in Glioblastoma Multiforme: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1846&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/865
dc.legacy.embargo2016-08-08T00:00:00-07:00
dc.identifier.contextkey9411818
refterms.dateFOA2022-08-26T04:22:53Z
html.description.abstract<p>Glioblastoma multiforme (GBM) is a deadly grade IV brain tumor characterized by a heterogeneous population of cells that are drug resistant, aggressive, and infiltrative. The current standard of care, which has not changed in over a decade, only provides GBM patients with 12-14 months survival post diagnosis. We asked if the addition of a novel endoplasmic reticulum (ER) stress inducing agent, JLK1486, to the standard chemotherapy, temozolomide (TMZ), which induces DNA double strand breaks (DSBs), would enhance TMZ’s efficacy. Because GBMs rely on the ER to mitigate their hypoxic environment and DNA repair to fix TMZ induced DSBs, we reasoned that DSBs occurring during heightened ER stress would be deleterious.</p> <p>Treatment of GBM cells with TMZ+JLK1486 decreased cell viability and increased cell death due to apoptosis. We found that TMZ+JLK1486 prolonged ER stress induction, as indicated by elevated ER stress marker BiP, ATF4, and CHOP, while sustaining activation of the DNA damage response pathway. This combination produced unresolved DNA DSBs due to RAD51 reduction, a key DNA repair factor. The combination of TMZ+JLK1486 is a potential novel therapeutic combination and suggests an inverse relationship between ER stress and DNA repair pathways.</p>
dc.identifier.submissionpathgsbs_diss/865
dc.contributor.departmentBiochemistry and Molecular Pharmacology
dc.description.thesisprogramInterdisciplinary Graduate Program


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