Novel molecular targets in advanced prostate cancer

Abstract

Prostate Cancer (PCa) is the most commonly diagnosed cancer in men and a leading cause of morbidity and mortality among men in the United States and Western Europe. The aim of initial treatment in advanced PCa is to reduce circulating levels of androgens in the body by blocking their effect through inhibiting the androgen receptor (AR) through androgen deprivation therapy (ADT). Additional agents that target the AR can be used when disease progresses on ADT. A number of patients will not respond to these agents, while others will eventually develop secondary resistance. Identifying those patients who will not respond to these agents is a key focus of ongoing research. In the study, the safety and tolerability of radium-223 combined with enzalutamide was assessed in patients with castration-resistant PCa (CRPC). Both these drugs are approved for use as single agents, however the safety of combining the drugs is unknown. In this study, it was found that the combination was safe and tolerable. The effect of the combination therapy on circulating tumour cells (CTCs) was also assessed, however it did not serve as a potential surrogate marker of response. PCa tends to have a long natural history and may require treatment with multiple modalities over many years, however repeat biopsies are not routine in the clinical setting. To address this, patients with metastatic PCa were enrolled in a translational study named iPROSPECT. All patients were offered an optional biopsy which could be either a bone marrow biopsy or a CT guided biopsy. It was observed that image guided biopsies provided more information than bone marrow biopsies and were more accurate at obtaining tissue. These tissue biopsies were further analysed using next generation sequencing (NGS) and compared to their primary biopsies. A number of gene targets were identified, with a higher incidence of mutations detected in patients with more advanced disease. Furthermore, gene expression differed between primary and metastatic biopsies indicating the significance of performing repeat biopsies in patients with advanced PCa. Similarly, having access to repeat biopsy material in advanced PCa allows for further testing using immunohistochemistry (IHC) which can identify alterations in the AR such as AR-V7 or neuroendocrine differentiation. In this study, both AR-V7 and neuroendocrine differentiation were noted in patients who had undergone a biopsy of a metastatic deposit. This underscores the importance of repeat biopsy, given that it could guide clinical decision making. To further identify biomarkers in advanced PCa, circular RNAs (circRNAs) were profiled in a cell line model of the disease. circRNAs are a novel type of non-coding RNA which appear to have a role in regulating microRNAs (miRNAs) and may have a role in cancer initiation and resistance to treatment. This study profiled PCa and benign cell lines and found circRNAs to be differentially expressed between malignant and benign cell lines and between androgen dependent and independent cell lines. Furthermore, hsa_circ_0004870 appears to be associated with AR-V7 and may play a role in the development of resistance to enzalutamide. The data generated in this project determined the combination of radium233 and enzalutamide is safe and well tolerated and has identified new therapeutic targets in advanced PCa. Therefore, this could lead to real world clinical benefits for patients living with this disease.