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" Combination of Novel Androgen Receptor Signalling Inhibitors with Radiation Therapy in Prostate Cancer "
Ghashghaei, Maryam
Niazi, Mohammad Tamim
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Latin Dissertation
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| Language of Document
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English
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| Record Number
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1058673
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| Doc. No
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TL57790
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| Main Entry
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Ghashghaei, Maryam
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| Title & Author
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Combination of Novel Androgen Receptor Signalling Inhibitors with Radiation Therapy in Prostate Cancer\ Ghashghaei, MaryamNiazi, Mohammad Tamim
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| College
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McGill University (Canada)
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| Date
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2019
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| Degree
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Ph.D.
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2019
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| Note
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284 p.
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| Abstract
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Prostate cancer (PCa) is the fifth leading cause of cancer-related deaths amongst men worldwide. Androgen deprivation therapy (ADT) in combination with radiation therapy (XRT) is the standard of care for high-risk localized PCa. Unfortunately, most patients become resistant to ADT due to continued androgen receptor (AR) signalling pathway. The goal of this thesis was to investigate whether enzalutamide, a secondgeneration AR antagonist, enhances the effect of radiation in PCa cells. Enzalutamide is an AR signalling inhibitor that not only blocks binding of androgens to the AR but is also shown prevents its translocation to the nucleus, DNA binding, and subsequent transcriptional activation of target genes in PCa cells. We have shown that enzalutamide increased the radiosensitivity of PCa cells significantly more than ADT. Enzalutamide sensitized hormone-sensitive PCa cells to XRT through increased levels of DNA damage and impaired the DNA repair process. Furthermore, concurrent administration of enzalutamide and radiation led to a maximal radiosensitivity when compared to either drug administration prior or after XRT. Thoroughly understanding the mechanism of radiosensitivity could assist in finding novel prognostic biomarkers and/or potential drug targets of radiosensitivity. These biomarkers may be used to predict the treatment outcomes and to identify radiation-resistant PCa patients. To identify radiosensitivity gene signatures induced by enzalutamide, we performed gene expression profiling following treatment of hormonesensitive (LNCaP) and hormone-resistant (C4-2) PCa cell lines. We identified that enzalutamide alone or in combination with ADT enhanced the effect of XRT through immune and inflammation-related pathways in LNCaP cells and metabolic-related pathways in C4-2 cells. Moreover, the Kaplan–Meier survival curves generated from the cancer genome atlas prostate adenocarcinoma (TCGA PRAD) dataset showed that the low expression of the candidate genes in patients with PCa correlated with disease recurrence and poor patient prognosis. Taken together, our pre-clinical results suggest that the combination of enzalutamide and XRT may be a new treatment option at an early-stage of PCa. The possibility of this treatment option is supported by ongoing clinical trials for patients with intermediate-risk disease. Furthermore, we identified potential predictive and/or prognostic biomarkers for response to combined AR inhibitor and XRT therapy. These biomarkers require further validation in clinical trials before they can be incorporated into clinical practice.
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| Descriptor
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Androgens
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Cancer therapies
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Deoxyribonucleic acid--DNA
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DNA repair
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Endocrine therapy
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Metastasis
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Oncology
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Prostate cancer
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Radiation therapy
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Survival analysis
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| Added Entry
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Niazi, Mohammad Tamim
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| Added Entry
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McGill University (Canada)
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