Repurposing Simvastatin as a Therapeutic Strategy to Treat p53 Mutant Solid Tumors

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dc.contributor.advisorPetrik, Jim
dc.contributor.authorPereira, Madison
dc.date.accessioned2023-01-05T16:00:42Z
dc.date.available2023-01-05T16:00:42Z
dc.date.copyright2022-12
dc.date.created2022-12-20
dc.degree.departmentDepartment of Biomedical Sciencesen_US
dc.degree.grantorUniversity of Guelphen
dc.degree.nameDoctor of Philosophyen_US
dc.degree.programmeBiomedical Sciencesen_US
dc.description.abstractFor the past 30 years, the standard of care for epithelial ovarian cancer has essentially remained unchanged with little progress in the development of novel innovative treatments. As such, new treatments beyond traditional chemotherapy are desperately needed. High-grade serous carcinoma (HGSC) originates in the distal fallopian tube and is the most prevalent and aggressive form of epithelial ovarian cancer. HGSC is characterized by a gain-of-function mutation in the TP53 gene, which is associated with numerous pro-tumorigenic processes including activation of the mevalonate pathway. The reprogramming of metabolic pathways is now recognized as a hallmark of cancer. The mevalonate pathway is a two-pronged metabolic system known for its role in cholesterol production and regulation of small GTPase prenylation, both of which are known to contribute to the development of HGSC. Statin drugs selectively block the mevalonate pathway by competitively inhibiting the pathway’s rate-limiting enzyme, HMG-CoA reductase. In light of this, there is evidence that individuals on statin drugs have a reduced incidence of some cancers, but further research is warranted to better characterize this. As it is now widely accepted that HGSC originates in the distal fallopian tube epithelium, the goal of this current thesis was to investigate the relationship between p53 status (wild-type, p53R175H mutant, Trp53 gene knockout) and mevalonate pathway signaling of murine oviductal epithelial (OVE) cells. We demonstrated that p53R175H mutant and Trp53 gene knockout OVE cells greatly expressed the mevalonate pathway compared to wild-type p53 OVE cells, and p53R175H mutant OVE cells progressed to advanced-stage HGSC in vivo. We also demonstrated significant regression of ovarian cancer disease burden and increased apoptosis following simvastatin treatment, however, simvastatin did not specifically impact mevalonate pathway signaling. In a similar manner, pancreatic cancer is another solid tumor characterized by TP53 mutations and has seen little progress in the development of effective therapies. Similar to our HGSC model, simvastatin proved to reduce pancreatic cancer disease burden, increase apoptotic tumor cell death and increase immune cell infiltration within the tumor microenvironment in vivo. In the future, the integration of statins into a multimodal approach may substantially improve the way we treat p53 mutant solid tumors and prevent the recurrence of disease to ultimately improve patient survival.en_US
dc.description.sponsorshipCanadian Institutes of Health Research (CIHR)
dc.description.sponsorshipOvarian Cancer Canada
dc.description.sponsorshipLondon Regional Cancer Program
dc.identifier.citationPereira M, Matuszewska K, Glogova A, Petrik J. Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy. Cancers. 2022 Jul 18, 14;3500. doi: 10.3390/cancers14143500
dc.identifier.citationPereira M, Matuszewska K, Jamieson C, Petrik J. Characterizing Endocrine Status, Tumor Hypoxia and Immunogenicity for Therapy Success in Epithelial Ovarian Cancer. Front Endocrinol (Lausanne). 2021 Nov 17, 12:772349. doi: 10.3389/fendo.2021.772349
dc.identifier.urihttps://hdl.handle.net/10214/27368
dc.language.isoenen_US
dc.publisherUniversity of Guelphen
dc.rights.licenseAll items in the Atrium are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectepithelial ovarian canceren_US
dc.subjecthigh-grade serous carcinomaen_US
dc.subjectpancreatic canceren_US
dc.subjectpancreatic ductal adenocarcinomaen_US
dc.subjectp53en_US
dc.subjectmutant p53en_US
dc.subjectmevalonate pathwayen_US
dc.subjectsimvastatinen_US
dc.subjectpre-clinical mouse modelen_US
dc.titleRepurposing Simvastatin as a Therapeutic Strategy to Treat p53 Mutant Solid Tumorsen_US
dc.typeThesisen
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