Prostate cancer is the second most common cancer among men worldwide. In Australia, it accounted for over 24,000 diagnoses in 2022, making it the most prevalent cancer and a leading cause of cancer-related deaths. Up to 45% of patients with prostate cancer progress to treatment-refractory or castrate-resistant prostate cancer (CRPC), with 90% developing bone metastasis. Current therapies for bone metastasis are largely palliative and offer limited curative options.
While the mechanisms that induce the outgrowth of dormant disseminated tumour cells in bone remain incompletely understood, evading immune surveillance is a critical factor in this process. Our laboratory has established a link between poor immunogenicity of bone metastases and the loss of type I interferon (IFN) signalling - a pathway essential to the induction of innate and adaptive immunity.
This project aims to identify the key mediators of IFN loss in prostate cancer bone metastases to discover novel druggable targets, which when modulated, can safely restore IFN signalling and enhance anti-tumour immunity within the bone niche. We have derived mouse RM-1 prostate cancer cell lines from established primary tumours and bone metastases that have been transduced to express an IFN-stimulated response element (ISRE) reporter system. These cells express GFP upon activation of the IFN pathway, allowing us to conduct high throughput drug screens to identify epigenetic drugs capable of restoring IFN signalling. This system has proven to be highly sensitive to stimulation with the TLR3 agonist, PolyI:C. Human prostate carcinoma cell lines and patient-derived organoids (PDO) will be used to validate the IFN-inducing activity of select drugs. In vivo mouse models of metastatic prostate cancer will further evaluate the therapeutic potential of identified drug candidates. As an extension to this work, we are conducting CRISPR screening to identify genes that play a role in IFN loss, which could be targeted to increase immunogenicity of bone metastases and improve their response to conventional and immune-based therapies. This study has the potential of facilitating the development of personalized treatment strategies for bone metastasis.