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Cover for The Molecular Determinants of Tumor Cell Sensitivity and Resistance to Antibody-Dependent Cellular Cytotoxicity (ADCC)
dc.contributor.advisorWeiner, Louis Men
dc.creatoren
dc.date.accessioned2013-09-12T18:23:25Zen
dc.date.available2014-03-12T04:10:09Zen
dc.date.created2013en
dc.date.issueden
dc.date.submitted01/01/2013en
dc.identifier.otherAPT-BAG: georgetown.edu.10822_559513.tar;APT-ETAG: 3d0b71458d4bfc84bbe0c7dc07d8dc10; APT-DATE: 2017-01-30_12:23:28en
dc.identifier.urien
dc.descriptionPh.D.en
dc.description.abstractMonoclonal antibodies represent the vanguard of targeted therapy due to their specificity and versatility. Aside from disrupting tumor cell survival and proliferation through cell surface receptor interactions, antibodies can induce antibody-dependent cellular cytotoxicity (ADCC) through immune effector cells, such as natural killer (NK) cells. Although clinical evidence suggests a role for ADCC in antibody therapy of cancer, molecular determinants of sensitivity and resistance to ADCC have not been well characterized. As resistance to antibody therapy is common, we aimed to uncover molecular determinants of ADCC response. We utilized two approaches to assess sensitivity and resistance, respectively, in an in vitro model system consisting of an NK-like cell line (NK92-CD16V), an anti-EGFR monoclonal antibody (cetuximab), and EGFR-expressing A431 cells.en
dc.description.abstractWe screened 60 genes from an EGFR gene network by RNA interference (RNAi) to assess for genes whose knockdown enhanced ADCC. First, we developed a high-throughput siRNA-based functional genomics screening platform for assessing ADCC. Primary and secondary screens identified three genes whose knockdown enhanced ADCC: GRB7, PRKCE, and ABL1. Characterization studies of these three genes revealed different putative mechanisms by which knockdown enhanced ADCC. We focused our efforts on ABL1, as c-Abl represents a highly translational target. ABL1 knockdown reduced the proliferation of A431 cells, in addition to its effects on enhanced ADCC. Inhibition of c-Abl kinase activity enhanced ADCC, phenocopying the effects of ABL1 knockdown and providing pre-clinical evidence for combining c-Abl inhibitors and cetuximab.en
dc.description.abstracten
dc.description.abstractWe also derived an ADCC-resistant cell population, A431/ADCCR, by successive ADCC treatment of A431 cells. Characterization of A431/ADCCR cells revealed reduced EGFR expression, diminished cell proliferation, and distinctive morphology compared to parental A431 cells. Whole genome gene expression analysis revealed over 330 differentially-expressed genes in A431/ADCCR cells. Generation and characterization of the A431/ADCCR cell line has yielded a valuable tool for probing resistance to ADCC, particularly acquired resistance through loss of EGFR.en
dc.description.abstractTogether, these two complementary approaches have revealed molecular determinants of sensitivity and resistance to ADCC. Enhancing tumor sensitivity to ADCC could translate into increased monoclonal antibody efficacy in the clinic, while unraveling resistance could inform therapeutic advances in the future.en
dc.formatPDFen
dc.format.extent160 leavesen
dc.languageenen
dc.publisherGeorgetown Universityen
dc.sourceGeorgetown University-Graduate School of Arts & Sciencesen
dc.sourceTumor Biologyen
dc.subjectADCCen
dc.subjectEGFRen
dc.subjectmonoclonal antibodyen
dc.subjectNK cellen
dc.subjectresistanceen
dc.subjectsensitivityen
dc.subject.lcshCytologyen
dc.subject.lcshImmunologyen
dc.subject.lcshMolecular biologyen
dc.subject.otherCellular biologyen
dc.subject.otherImmunologyen
dc.subject.otherMolecular biologyen
dc.titleThe Molecular Determinants of Tumor Cell Sensitivity and Resistance to Antibody-Dependent Cellular Cytotoxicity (ADCC)en
dc.typethesisen
gu.embargo.terms6-monthsen


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