Determining the functional consequences of Rb/p53 loss and androgen deprivation in prostate cancer

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Thesis type
(Thesis) M.Sc.
Date created
Author: Lo, Raymond
Prostate cancer (PCa) is the most diagnosed cancer for men in Canada, accounting for roughly 20% of new cancer cases annually. Androgen-directed therapies such as androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSIs) remains the standard of care for controlling prostate cancer. Although initially effective, most patients eventually develop castration-resistant prostate cancer (CRPC), an androgen-independent disease. The onset of drug-resistance and metastasis in CRPC ultimately results in an incurable and fatal disease. Notably, CRPC possesses a unique genetic landscape where the retinoblastoma tumor suppressor protein (Rb) and tumor suppressor protein P53 (p53) are commonly mutated. We hypothesize Rb-loss alone or in concert with p53 are drivers of PCa transformation towards metastatic CRPC (mCRPC). To test this hypothesis, we used the CRISPR-Cas9 gene-editing system to knockout Rb and p53 expression in LNCaP human prostate cancer cells. Cell viability assays reveal concurrent loss of Rb/p53 confers resistance to enzalutamide compared to control and single knockout cells. Additionally, gene expression and immunoblot analysis identified significant upregulation of neuroendocrine markers in Rb/p53 knockout cells while migration assays show increased migratory potential. The results presented here give us greater insight into the development of CRPC and could serve as the basis for new targeted therapies for advanced metastatic prostate cancer.
127 pages.
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Thesis advisor: Beischlag, Timothy
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