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UBC Theses and Dissertations

BIRC6 as novel therapeutic target in advanced prostate cancer : clinical relevance, development of potential therapeutic agents & preclinical drug efficacy Luk, Sze Ue

Abstract

The lack of effective therapy for advanced prostate cancer (PCa) remains a major unmet clinical need. Recently approved therapeutics, such as enzalutamide (ENZ), have only delayed the inevitable progression of castration-resistant PCa (CRPC), as resistance will typically emerge following treatment. Although increased apoptosis-resisting ability of cancer cells represents a fundamental mechanism for the onset of treatment resistance, no relevant agents have yet been developed. Preliminary work in our laboratory has revealed an association between elevated expression of BIRC6, an Inhibitor of Apoptosis (IAP) protein, and advanced PCa. The overall objective of this doctoral study is to investigate the roles of BIRC6 in advanced PCa, and to assess the therapeutic efficacy of a novel anti-BIRC6 agent. Firstly, I evaluated the clinical relevance of BIRC6 using patients’ PCa specimens, and the functional importance of BIRC6 using cell line-based PCa models. A significant correlation was found between elevated BIRC6 protein expression in clinical PCa and poor patient prognostic factors. Functional assays validated the importance of BIRC6 in PCa cell proliferation and apoptosis suppression. Next, I designed BIRC6-based, dual IAP-targeting antisense oligonucleotides (dASOs) to inhibit BIRC6 and an additional IAP. Two dASOs, 6w2 and 6w5 targeting BIRC6+cIAP1 and BIRC6+survivin, showed substantial inhibition of CRPC cell proliferation in vitro and in vivo. Functional studies showed that both dASOs significantly induced apoptosis, cell cycle arrest and suppression of NFκB activation in CRPC cells. Finally, I assessed the growth-inhibitory efficacy of dASO-6w2 in ENZ-resistant CRPC, which has become an increasingly prominent problem in the clinic. The efficacy of dASO-6w2 was studied using both ENZ-resistant PCa cell lines and a clinically relevant, transplantable patient-derived xenograft PCa tissue model, designated LTL-313BR, which exhibits primary ENZ resistance. Importantly, I showed that treatment with dASO-6w2 markedly suppressed the growth of LTL-313BR xenografts. The dASO-6w2 was also found to increase tumour apoptosis and inhibit the expression of several pro-survival genes that were up-regulated in the LTL-313BR line. In conclusion, this doctoral study has established the clinical relevance and functional importance of BIRC6 in advanced PCa, and has also presented new BIRC6-targeting agents that markedly suppress the growth of advanced PCa.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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