Development of Oncolytic Adenoviruses for the Management of Prostate Cancer

Abstract

Prostate cancer (PCa) is the fifth most common cause of cancer-related deaths in men globally. Androgen receptor (AR) signalling plays a vital role in initiation and progression and antiandrogens are standard of care first-line therapeutics. However, resistance frequently develops resulting in metastatic castration-resistant prostate cancer (mCRPC). Management of CRPC is currently chemotherapy and/or radiotherapy but is mostly palliative due to rapid development of resistance. The need for novel approaches to eliminate mCRPC is compelling; a promising option is replication-selective (oncolytic) adenoviruses with demonstrated efficacy in preclinical models of multidrug-resistant PCa. The safety of various viral mutants has been confirmed in numerous clinical trials with minimal toxicity in patients. Importantly, oncolytic adenoviruses synergise with the current standard of care for mCRPC even in treatment-resistant cells. In early phase I–II clinical trials, promising efficacy in patients with localised PCa was reported after intratumoural administration, and phase III trials are underway. To enable systemic delivery, for targeting of mCRPC, further developments are necessary because of the short half-life of the adenoviral mutants in human blood. Current progress in preventing the high- affinity binding of adenovirus to erythrocytes, hepatocyte uptake, and elimination by hepatic Kupffer cells will be described.