A Viral Mimicry Approach to Target Prostate Cancer
Abstract
Although strides have been made in the clinical management of prostate cancer, most patients with hormone-refractory recurrent or overt distant metastases are incurable. Treatment options for these patients are primarily restricted to toxic chemotherapy and pain management. Even with aggressive treatment, the 5-year survival rate for patients with metastatic prostate cancer is only ~30%. Therefore, there is an unmet clinical need to develop innovative, more effective, and less toxic treatment options for these patients. In this proposal, we explore an entirely new way to target metastatic prostate cancer by awakening ancient viruses in the DNA of prostate cancer cells. This approach, which has been termed by us and others as viral mimicry, has the potential for widespread clinical applications in metastatic prostate cancer treatment as a standalone therapy and enhancer of certain antitumor therapies, including PARP inhibitor and immune checkpoint blockade (ICB) therapies. Ancient viruses compose ~40% of the human genome and are normally transcriptionally silenced in our cells. We discovered that a histone methyltransferase called SUV39H1 is essential for the silencing of ancient viruses in prostate cancer cells. SUV39H1 inhibition, such as through treatment with the newly developed drug F5446, reactivated these ancient viruses in prostate cancer cells, which stimulated viral defense pathways that normally function to protect cells from infection by exogenous pathogens (e.g., viruses). F5446 also promoted DNA replication stress, stimulated interferon (IFN) signaling, and potently killed prostate cancer cells in vitro. Importantly, SUV39H1 was found not to be required for ancient virus silencing in normal cells, indicating a therapeutic window for metastatic prostate cancer treatment. In this study, we will evaluate three potential therapeutic applications for F5446 in metastatic prostate cancer treatment: (1) as a standalone therapy through induction of DNA replication stress and natural killer (NK) cell cytotoxicity; (2) synergy with ICB therapy through stimulation of IFN signaling and cytotoxic T cell tumor infiltration; and (3) as an enhancer of PARP inhibitor antitumor activity through induction of DNA replication stress in prostate cancer cells. Validation of efficacy of F5446 in any of these therapeutic applications could revolutionize the way that metastatic prostate cancer patients are treated, which would undoubtedly have a significant impact on reducing disease mortality. Moreover, we are actively developing more potent and selective SUV39H1 inhibitors, suggesting that the results of this study could be rapidly translated into the clinic for prostate cancer patient care in a 2-3-year time frame.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310135
Entities
People
- Charles Spruck
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army