Does RIPK2 Promote Prostate Cancer Progression by Activating the Max:Myc and Onecut2 Pathways?
Abstract
Prostate Cancer is the most common non-skin cancer in American man. It was estimated that 161,360 American men will be diagnosed with prostate cancer, and 26,730 men will die of the disease in year 2017. Though most prostate tumors are indolent (with very slow growth rates) and do not affect patients’ lives, a significant portion of prostate cancer is aggressive and can develop into lethal disease. At present, it is still not well understood what makes prostate cancer cells more aggressive, and there are no effective strategies to delay or abolish the progression of aggressive prostate cancer into lethal stages, such as metastatic castration-resistant prostate cancer (mCRPC) and cancers in the neuroendocrine spectrum (NEPC). Recently, using multidisciplinary techniques, we found that receptor-interacting serine-threonine kinase 2 (RIPK2) is potentially very important for the progression of prostate cancer and discovered that RIPK2 might execute its functions by activating two prostate cancer-promoting pathways, namely, the MAX:MYC and ONECUT2 pathways. The goal of this study is to experimentally determine whether RIPK2 does promote prostate cancer progression by activating the MAX:MYC and ONECUT2 pathways. To achieve our goal, I will use a variety of biotechniques, including gene cloning and editing, cell assays, mouse models, and phosphoproteomics. If successful, the proposed study will establish the kinase RIPK2 as a high-value target in aggressive prostate cancer and provide a molecular signature that can identify aggressive prostate cancer. Our preliminary studies suggest that about one third of aggressive prostate cancers express high levels of RIPK2. This subpopulation of patients may benefit from RIPK2-targeting therapies. Notably, three Food and Drug Administration-approved drugs were recently found to be potent inhibitors of RIPK2. These drugs may be rapidly repurposed to benefit many prostate cancer patients who can be effectively selected by measuring the RIPK2 pathway activities in biopsies. In addition to the clinical significance, the proposed study will also help us to better understand the molecular basis of prostate cancer progression. My career goal is to become an independent investigator in prostate cancer translational research and cancer proteomics research, with a strong focus on finding reliable protein biomarkers and drug targets for clinical translation. The research plan will greatly improve my scientific perspectives on translational cancer research, as well as many research skills, including project management, troubleshooting, collaboration, networking, data presentation, manuscript writing, and grant application. My primary mentor, Dr. Freeman, is the Ben Maltz Chair in Cancer Therapeutics and a full Professor at Cedars-Sinai Medical Center and the University of California, Los Angeles. He has a long track record (>25 years) of research mentoring and has trained over 60 fellows, many of whom now serve as independent investigators in prestigious universities or institutes. My co-mentor, Dr. Yang, is a leader in the field of cancer proteomics and has extensive experience with quantitative proteomics and phosphoproteomics. I believe that, supported by the Department of Defense Prostate Cancer Research Program Early Investigator Award and mentored by Drs. Michael Freeman and Wei Yang, the training program will greatly facilitate my transition into an independent investigator and help me achieve my career goal in the long run.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810476
Entities
People
- Yiwu Yan
Organizations
- Cedars-Sinai Medical Center
- United States Army