Show simple item record

dc.contributor.advisorMeuillet, Emmanuelle J.en_US
dc.contributor.authorMoses, Sylvestor Andrea
dc.creatorMoses, Sylvestor Andreaen_US
dc.date.accessioned2013-06-10T19:37:33Z
dc.date.available2013-06-10T19:37:33Z
dc.date.issued2013
dc.identifier.urihttp://hdl.handle.net/10150/293751
dc.description.abstractPleckstrin homology (PH) domains are structurally conserved domains, which generally bind to phosphatidylinositol phosphate (PtdInsP) lipids. They are present in a variety of proteins, including those that are upregulated in cancer growth and metastasis, and represent a crucial component of intracellular signaling cascades and membrane translocation. Thus, they may be considered as attractive targets for cancer drug therapy. AKT (protein kinase B), a pleckstrin homology lipid binding domain and a serine/threonine kinase-containing protein, is a key component of the phophatidylinositol-3-kinase (PI3K)/AKT cell survival signaling pathway which is activated in a variety of cancers, including prostate, pancreatic, and skin cancers. In this study, I report the finding of a novel inhibitor of AKT; PH-427. I describe its effects on binding to the PH domain of AKT thus preventing its binding to PtdIns3-P at the plasma membrane and subsequent activation. In vivo testing of the drug led to reduction of tumor size and numbers in a mouse pancreatic cancer model. Additional testing of PH-427 on squamous cell carcinomas revealed that the drug is able to reduce tumor burden and multiplicity in vivo when topically applied. Thus, we demonstrate proof-of-principle in targeting PH domains as a viable cancer drug therapy option. The effects of PH-427 raised the intriguing possibility that targeting PH domains may have beneficial effects in other signaling pathways with PH domain-containing proteins. Guanine exchange factors (GEFs) contain a Dbl homology (DH) domain and a PH domain and have been shown to be involved in the process of metastasis. More specifically, RacGEFs activate Rac1 GTPase by facilitating the exchange of GDP to GTP. Over-expression of certain GEFs has been shown to contribute to increased malignancy in a variety of cancers. T-lymphoma invasion and metastasis-inducing protein-1 (Tiam1) is a highly conserved GEF and contains an N-terminal pleckstrin homology domain (nPH) and a DH/C-terminal PH domain (cPH). Tiam1 has been found to be over-expressed in several cancers, including breast, colon and prostate cancers. In this study, I describe the identification, development, experimental testing, and potential mechanism of action of novel small molecule inhibitors targeting the RacGEF Tiam1 to inhibit prostate cancer bone metastasis.
dc.language.isoenen_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.subjectDrug Discoveryen_US
dc.subjectMetastasisen_US
dc.subjectPleckstrin Homology Domainsen_US
dc.subjectSmall Molecule Inhibitorsen_US
dc.subjectTiam1en_US
dc.subjectMolecular & Cellular Biologyen_US
dc.subjectAkten_US
dc.titleTargeting Pleckstrin Homology Domains for the Inhibition of Cancer Growth and Metastasisen_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.contributor.committeememberHeimark, Ronald L.en_US
dc.contributor.committeememberSchroeder, Joyce A.en_US
dc.contributor.committeememberTsao, Tsu-Shuenen_US
dc.contributor.committeememberMeuillet, Emmanuelle J.en_US
dc.description.releaseRelease after 09-Nov-2013en_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineMolecular & Cellular Biologyen_US
thesis.degree.namePh.D.en_US
refterms.dateFOA2013-11-09T00:00:00Z
html.description.abstractPleckstrin homology (PH) domains are structurally conserved domains, which generally bind to phosphatidylinositol phosphate (PtdInsP) lipids. They are present in a variety of proteins, including those that are upregulated in cancer growth and metastasis, and represent a crucial component of intracellular signaling cascades and membrane translocation. Thus, they may be considered as attractive targets for cancer drug therapy. AKT (protein kinase B), a pleckstrin homology lipid binding domain and a serine/threonine kinase-containing protein, is a key component of the phophatidylinositol-3-kinase (PI3K)/AKT cell survival signaling pathway which is activated in a variety of cancers, including prostate, pancreatic, and skin cancers. In this study, I report the finding of a novel inhibitor of AKT; PH-427. I describe its effects on binding to the PH domain of AKT thus preventing its binding to PtdIns3-P at the plasma membrane and subsequent activation. In vivo testing of the drug led to reduction of tumor size and numbers in a mouse pancreatic cancer model. Additional testing of PH-427 on squamous cell carcinomas revealed that the drug is able to reduce tumor burden and multiplicity in vivo when topically applied. Thus, we demonstrate proof-of-principle in targeting PH domains as a viable cancer drug therapy option. The effects of PH-427 raised the intriguing possibility that targeting PH domains may have beneficial effects in other signaling pathways with PH domain-containing proteins. Guanine exchange factors (GEFs) contain a Dbl homology (DH) domain and a PH domain and have been shown to be involved in the process of metastasis. More specifically, RacGEFs activate Rac1 GTPase by facilitating the exchange of GDP to GTP. Over-expression of certain GEFs has been shown to contribute to increased malignancy in a variety of cancers. T-lymphoma invasion and metastasis-inducing protein-1 (Tiam1) is a highly conserved GEF and contains an N-terminal pleckstrin homology domain (nPH) and a DH/C-terminal PH domain (cPH). Tiam1 has been found to be over-expressed in several cancers, including breast, colon and prostate cancers. In this study, I describe the identification, development, experimental testing, and potential mechanism of action of novel small molecule inhibitors targeting the RacGEF Tiam1 to inhibit prostate cancer bone metastasis.


Files in this item

Thumbnail
Name:
azu_etd_12768_sip1_m.pdf
Size:
51.70Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record