Targeting RNA-Binding Protein HuR as a Novel Therapy for Lethal Prostate Cancer
Abstract
In the past decades, a lot of efforts have been made on diagnosis and treatment of prostate cancer. Yet, prostate cancer is still the most commonly diagnosed cancer in men (accounting for 19% of newly diagnosed cancers) and is the second most common cause of male death from cancer. The American Cancer Society estimates that, in 2020, approximately 164,690 men in the U.S. will be diagnosed with prostate cancer and 33,330 will die from it. The 5-year relative survival rate is approaching 100% among patients diagnosed with localized or regional disease. However, the mean survival time for castration-resistant prostate cancer (CRPC) is only 1-2 years. Metastasis is another reason that causes the high mortality of prostate cancer. The 5-year survival rate for metastatic prostate cancer is less than 30%. Most of the current treatment options do not work very well for metastatic prostate cancer, including the immunotherapy, which uses a person’s immune system to fight cancer and has been working very well in many other types of cancer. There is unmet medical need for lethal prostate cancer. Lethal prostate cancer is very resistant to chemotherapy, radiation therapy or immunotherapy, due to the overexpression of the various tumor-driving proteins. Current and future efforts toward designing and developing new therapies specifically target those oncoproteins that confer prostate cancer cell growth and metastasis. This strategy of developing molecularly targeted therapies will improve survival and quality of life of prostate cancer patients by increasing specificity and reducing toxicity. One such oncoprotein, Human antigen R (HuR), has drawn increased attention. HuR is a tumor-promoting protein and is overexpressed in many types of cancers, including prostate cancer. More significantly, CRPC and metastatic prostate cancers have higher levels of HuR than primary tumors. HuR is an RNA-binding protein that specifically binds the target mRNAs and promotes or increases the translation of target genes that are known tumor-driving/promoting genes, or oncogenes. These oncogenes are implicated in different tumor processes including cell proliferation, cell survival, angiogenesis, invasion, metastasis, and immune evasion. Taken together, HuR is a promising therapeutic target for lethal prostate cancer. In our effort to discover new drugs targeting HuR, we identified several potent small molecule compounds that inhibit HuR function. We hypothesize that small molecule HuR inhibitors will block HuR function, leading to inhibition of cell growth and tumor progression in prostate cancer cells with high levels of HuR. Cell studies will be used to determine the specificity of these compounds to HuR, and animal model studies will examine their anti-tumor activity in a prostate cancer animal models, including the human prostate tumor cells inoculated to mouse prostate (orthotopic tumor model) and to the tibia (bone metastasis model). So far, there is limited success in drug discovery for RNA-binding proteins, which are known to be “undruggable.” This study has the potential to be revolutionary by identifying and validating a new class of small molecule inhibitors targeting the undruggable but critical tumor-promoting protein, HuR. Discovery of such HuR inhibitors will provide promising lead compounds to develop novel molecular therapy targeting the oncoprotein HuR and will also provide potent and specific chemical probes for delineating the functional roles of HuR in prostate cancer initiation, progression, and immune suppression. Our ultimate goal is to obtain 1-2 lead compounds for further development as a whole new class of molecular cancer therapy that inhibit the lethal metastatic prostate cancer with high levels of HuR.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110573
Entities
People
- Xiaoqing Wu
Organizations
- United States Army
- University of Kansas