Unique effects of NDRG1 and novel thiosemicarbazones on androgen receptor signalling pathways in prostate cancer

Abstract

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second most common cause of cancer-related death among men worldwide and is expected to increase drastically in the near future. The androgen receptor (AR) remains the main driver for the progression and development of PCa. Despite advances in cancer detection and good initial response to current PCa treatment, inhibition of AR still leads to resistance in most men, leading to the development of metastatic castration resistant prostate cancer (CRPC), which remains incurable and ultimately fatal. As metastasis is responsible for the majority of cancer-related deaths, this outlines the urgent need to better characterise the mechanisms leading to CRPC and to develop novel treatment strategies to overcome this major clinical problem. This thesis proposes to investigate the efficacy of novel di-2-pyridylketone thiosemicarbazones, Dp44mT and DpC, as potential new candidates for the treatment of advanced PCa. The ability of these thiosemicarbazones to upregulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1) was particularly significant, with the molecular effects of NDRG1 in PCa being another major aim of this study. In conclusion, these comprehensive investigations identify a unique new approach to overcome androgen resistance in PCa, by simultaneously targeting both androgen-dependent and -independent arms of AR signalling via NDRG1. This is crucial in expanding our knowledge on the molecular function of NDRG1 as a metastatic suppressor. Further, I demonstrated that innovative thiosemicarbazones, Dp44mT and DpC, have the ability to affect several oncogenic signalling pathways of AR in PCa. This multifaceted approach has the potential overcome development of CRPC and is superior to current PCa therapies (i.e. enzalutamide) which mainly targets androgen-dependent AR signalling and ultimately suffers from development of resistance and recurrence.