Grant: Operating Grant

Prostate cancer often metastasizes to the bone where it predominantly forms blastic (bone forming) lesions that are associated with poor prognosis and mortality. Androgen ablation therapy is the only effective treatment for metastatic prostate cancer. Unfortunately, the disease ultimately develops resistance and becomes hormone refractory. Aberrant activation of the androgen receptor (AR) is the most suspected mechanism underlying resistance to hormonal therapy. The N-terminus of the AR (AR NTD), which is part of the AR and is known to enhance AR activity, is activated by factors other than androgens including those produced by osteoblasts such as interleukin-6 (IL-6). This and other indications led to the hypothesis that the AR NTD could be a drug target for the treatment of hormone refractory prostate cancer. We have previously presented in vivo evidence for the importance of the AR NTD as a drug target using human prostate cancer tumours grown in animal models. Experimental and clinical data suggest that IL-6 has an important role in hormonal progression of prostate cancer and that this is, at least in part, through the transactivation of the AR NTD. However, the in vivo function of the AR NTD and IL-6 has not been investigated in the context of the bone environment, and the mechanisms therein are poorly understood. The current proposal will address these issues and in the process will potentially validate IL-6 and/or AR NTD as drug targets for bone metastasis of prostate cancer.