Targeting steroid signalling pathways in hormone dependent cancer

© 2011 Dr. Matthew James FankhauserA sex hormone binding decoy protein made by fusing the ligand binding domain of the androgen receptor to an immunoglobulin Fc region or an elastin like polypeptide (ELP) was designed to bind circulating testosterone and other androgens, due to the high affinity of the androgen receptor ligand binding domain for the male sex hormones. Multiple cell based in vitro assays were designed and monitored for both growth and the biomarker, prostate specific antigen (PSA), with data confirming the decoy protein was able to inhibit the growth of hormone dependent prostate cancer cell lines and the androgen dependent expression of PSA. In vivo models were able to show the binding decoy protein was able to reduce free testosterone levels within a mouse, with further in vivo subcutaneous and orthotopic xenograft models of various prostate cancer stages demonstrated the ability of the binding decoy protein to reduce the growth and PSA expression of prostate tumours. Prostate cancer relies on circulating male hormones, in particular testosterone, to drive growth and proliferation of prostate tumour cells. This reliance on testosterone led to the development of novel therapeutics targeted at decreasing available testosterone, collectively termed Androgen Deprivation Therapy (ADT) and upon treatment resulted in decreased tumour growth. ADT is routinely used for treatment of prostate cancer; however the failure of current therapies to completely remove circulating testosterone and other androgens has been linked with the continued hormone dependence associated with the more aggressive form of disease, Castrate Resistant Prostate Cancer (CRPC). While the mechanisms involved in the progression of prostate cancer to the castrate resistant form of disease remain undetermined, the continued reliance on circulating hormones means new novel treatment options for the complete removal of circulating hormones could result in better outcomes and an increased life expectancy for prostate cancer patients. The establishment of a human trial demonstrated the potential for advanced prostate cancer specimens to produce testosterone and dihydrotestosterone (DHT) from an earlier precursor, androstenedione. The early data obtained from the human trial will be used to expand the study to obtain statistically significant numbers to help determine the mechanisms involved in the progression of prostate cancer to the castrate resistant phase. Due to the successful implementation of the decoy binding protein in the prostate cancer preclinical setting, preliminary in vivo orthotopic xenograft models were able to demonstrate the potential for the application of the drug therapy to be utilised in other hormone dependent cancers such as breast and ovarian. A modified version of the binding decoy protein was constructed with the ligand binding domain of the estrogen receptor for the use in estrogen driven diseases. The data obtained in this thesis has resulted in the submission of three separate patents