Prostate cancer is the second most common cause of cancer deaths in men in the US, with nearly 200,000 newly diagnosed cases per year, and 40,000 deaths per year. Despite advances in prevention and early detection, nearly 20' of newly diagnosed patients present with metastatic disease, which leads to the majority of prostate cancer mortalities. Another feared situation for advanced prostate cancer patients is to stop responding to androgen deprivation and develop androgen independent, hormone refractory disease, indicated by an upsurge of serum prostate-specific antigen (PSA). Once hormone deprivation treatment failS, no effective treatment is yet available for these patients. Hormone refractory disease progression and metastatic prostate cancer are not well understood, and a definitive diagnostic modality to study and detect these advanced stages of disease is lacking. The androgen and androgen receptor (AR) plays a central role in normal prostatic development and growth, and likely in prostate cancer progression. PSA, besides being an important disease marker, is dependent on AR for specific expression in normal and cancerous prostate. We exploit this property of PSA regulation and developed highly active and prostate-specific gene delivery vehicles, derived from a modified virus. We engineered our prostate-specific virus to deliver a light-producing gene, luciferase, derived from THE firefly. In doing so, we demonstrated this prostate-specific virus is able to specifically illuminate and locate disseminated lung and spinal prostate cancer cells in living mice.
In this application, we aim to apply an even more potent prostate-specific TSTA system to develop improved diagnostic and tumor killing approaches. We will use the exquisite specificity and high activity of our system to detect AI and metastatic lesions in living mice, covering several preclinical disease models. In the second aim, we will apply the TSTA system and re-engineer the viral replication process in such a way that it only replicates in a prostate-specific manner. In doing so, we aim to convert adenovirus into a direct killing tool to destroy prostate cancer. Our ultimate goal is to utilize the robust and prostate-specific TSTA targeting approach to develop novel, efficient diagnostic and therapeutic approaches to manage advanced, metastatic prostate cancer.