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dc.contributor.authorWilliams, Rodette
dc.contributor.otherQueen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))en
dc.date2016-09-30 09:04:48.785en
dc.date.accessioned2016-10-03T20:21:52Z
dc.date.issued2016-10-03
dc.identifier.urihttp://hdl.handle.net/1974/15047
dc.descriptionThesis (Master, Biomedical & Molecular Sciences) -- Queen's University, 2016-09-30 09:04:48.785en
dc.description.abstractBreast and ovarian cancers are among the leading causes of cancer related deaths in women worldwide. In a subset of these cancers, dysregulation of the human epidermal growth factor receptor 2 (HER2) leads to overexpression of the receptor on the cell surface. Previous studies have found that these HER2+ cancers show high rates of progression to metastatic disease. Metastasis is driven by cytoskeletal rearrangements that produce filamentous actin (F-actin) based structures that penetrate and degrade extracellular matrix to facilitate tumour invasion. Advancements in targeted therapy have made F-actin an attractive target for the development of new cancer therapies. In this thesis, we tested the actin-depolymerizing macrolide toxin, Mycalolide B (MycB), as a potential warhead for a novel antibody drug conjugate (ADC) to target highly metastatic HER2+ breast and ovarian cancers. We found that MycB treatment of HER2+ breast (SKBR3, MDA-MB-453) and ovarian (SKOV3) cancer cells led to loss of viability (IC50 values ≤ 64 nM). Sub-lethal doses of MycB treatment caused potent suppression of leading edge protrusions, migration and invasion potential of HER2+ cancer cells (IC50 ≤ 32 nM). In contrast, other F-actin based processes such as receptor endocytosis were less sensitive to MycB treatment. MycB treatment skewed the size of endocytic vesicles, which may reflect defects in F-actin based vesicle motility or maturation. Given that HER2+ cancers have been effectively targeted by Trastuzumab and Trastuzumab-based ADCs, we tested the effects of a combination of Trastuzumab and MycB on cell migration and invasion. We found that MycB/ Trastuzumab combination treatments inhibited motility of SKOV3 cells to a greater degree than either treatment alone. Altogether, our results provide proof-of-principle that actin toxins such as MycB can be used as a novel class of warheads for ADCs to target and combat highly metastatic cancers.en_US
dc.languageenen
dc.language.isoenen_US
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsCreative Commons - Attribution - CC BYen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectTargeted therapyen_US
dc.subjectMetastasisen_US
dc.subjectCanceren_US
dc.subjectHER2en_US
dc.subjectActinen_US
dc.subjectBreast canceren_US
dc.subjectOvarian canceren_US
dc.subjectNatural productsen_US
dc.titleTargeting the actin cytoskeleton in HER2+ metastatic cancer cells using a macrolide toxinen_US
dc.typeThesisen_US
dc.description.restricted-thesisWaiting to complete and publish thesis as a manuscripten
dc.description.degreeMasteren
dc.contributor.supervisorAllingham, Johnen
dc.contributor.supervisorCraig, Andrew W.en
dc.contributor.departmentBiomedical and Molecular Sciencesen
dc.embargo.terms1825en
dc.embargo.liftdate2021-10-02


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