Problem Addressed and Its Relevance to the Prostate Cancer Research Program: A large number of prostate cancer patients develop metastatic castrate-resistant prostate cancer. When this happens, there are no treatments that can reverse or cure these patients. Although there are encouraging clinic trials for using immunotherapy in cancer, success with this approach in prostate cancer has been modest. In this proposal, we will study ways to enhance immunotherapies for prostate cancer. Our work directly addresses the relevance of developing effective treatments for high-risk patients by understanding how the tumor influences the immune system and by identifying a new family of tumor specific targets that can be recognized and destroyed by the immune system.

How Is This Project Innovative? It has become increasingly clear that the immune system plays a key role in controlling prostate cancer. In order for the immune system to kill cancer cells, it must distinguish tumor cells from normal healthy cells. However, we have little information on what characteristics of prostate tumors are recognized by the immune system. Recent work in other cancers has shown that immune system can recognize mutations in the tumor. This proposal seeks to identify a new class of gene mutations called fusion genes and spliced variants that are found in patients who are at high risk of developing metastatic castration-resistant prostate cancer. Moreover, with this pilot study, we will begin to understand whether mutations influence the immune system in a similar or different manner between patients.

What Is the Impact if the Project Is Successful? The success of this proposal will lay important groundwork for developing immunotherapy strategies to treat prostate cancer. First, fusion genes or spliced variants are only found in tumors, unlike current immune-based approaches that rely on targeting genes found in both normal and tumor tissues (e.g., PMSA, PAP). Second, once an effective immune candidate is identified, multiple strategies can be used to develop an immunotherapy. For example, given the complexity of different immune therapies, post-radical prostectomy in high-risk patients would be an ideal group to give a therapeutic vaccine, while metastatic patients would be more suitable for adoptive T cell treatment. These findings will provide information about the best mutations to target and have broad relevance to other immune-approaches for the treatment of prostate cancer.