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UBC Theses and Dissertations

Studying the effect of OGX-225, a novel antisense therapy, on prostate cancer cells Alwaal, Amjad Hassan


Prostate cancer (PCa) is the most common malignancy diagnosed in Canadian men. If the disease is not detected early the patients would present with metastatic disease. Metastatic PCa represents a challenge for treatment. The primary treatment at this stage is androgen ablation (castration). However, metastatic PCa invariably progress to a castration-resistant form, which does not respond to androgen ablation. This form is a lethal form of the disease, and there are several strategies that have been described to treat this form of cancer. The Insulin-like Growth Factor (IGF) system plays a pivotal role in prostate development and castration-resistant progression. It is tightly regulated by seven high affinity Insulin-like Growth Factor Binding Proteins (IGFBP 1-7). IGFBP-2 and IGFBP-5 are over-expressed in PCa and play a role in castration-resistant progression, while IGFBP-3 is downregulated and inhibits growth of PCa cells. OGX-225 is a novel second- generation antisense drug (ASO) that targets both IGFBP-2 and IGFBP-5. M. Muramaki et al, at the prostate center in Vancouver, showed in their unpublished data that it inhibits the growth PCa cells both in vitro and in vivo, and that it downregulates IGFBP-2 and IGFBP-5. In my thesis, I showed the inability to rescue PCa cells exposed to OGX-225 by adding back IGFBP-5, indicating that the action of OGX-225 is irreversible and targets several targets in addition to IGFBP-2 and IGFBP-5. I also showed the growth inhibitory effect of IGFBP-3 through a mechanism other than apoptosis, while not having an additive effect on PCa cells when combined with OGX-225. This thesis reports the multi-targeting ability of OGX-225 resulting in the inability to rescue PCa cells exposed to it, and gives some insight into the mechanism of action of IGFBP-3 and its effect when combined with OGX-225.

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