Novel Use of microRNA-765 in Prostate Cancer-Directed RNA Therapy
Abstract
Prostate cancer (PCa) is a major health concern in men in the United States. It affects one out of seven men in their lifetime, accounting for the second most common cancer in men nationwide. Although early screening for elevated prostate serum antigen improved the prognosis, there is currently no cure for metastatic PCa. The need for devising an innovative approach for advanced metastatic PCa-specific therapeutic strategies aroused my interest in the PCa field. My training will involve intensive courses related to cancer cell biology and therapeutics, attending research seminars, tumor board meetings, networking at conferences, attending workshops to attain the state-of-art skills and techniques in the PCa field. Moreover, I will be trained in a well-equipped research environment, where researchers and clinicians actively interact to share opinions and resources, creating a productive PCa research environment. My primary mentor, Dr. Shuk-mei Ho, is an expert in endocrinology of PCa and has in place an environment conducive for training an independent researcher. My goal from this research program is to extend my scientific reasoning and critical thinking and to explore the use of small regulatory non-coding RNAs, namely microRNAs, as a tool for PCa-specific therapeutics. Fulvestrant, an antiestrogen approved by the Food and Drug Administration for treating primary prostate cancer, is well tolerated and can increase lifespan of metastatic PCa patients in a Phase II clinical trial. However, the effect is acute, receptor status dependent, and may risk drug resistance. To overcome these deficits, we focus on the tumor-suppressing ability of microRNAs associated with fulvestrant. MicroRNAs regulates expression of multiple oncogenes such as high mobility group AT hook 1 (HMGA1) and k-Ras to stop cancer cells from expanding and migrating. Our recent publication illustrates microRNA-765 inhibits the cancer cells from being aggressive. This highlights the possible therapeutic use of microRNA-765 in modulating prostate disease advancement and cancer metastasis. We hypothesize that microRNA-765 change the expression of multiple oncogenes including HMGA1, endothelial nitric oxide synthase, and neurotrophin tyrosine kinase 3 to attenuate PCas from growing and migrating. Dissecting the role of this unique set of microRNA-765 target genes will unveil how their change in expression and dysregulated signaling pathways alters PCa cell growth, migration, and sensitivity to therapeutic drugs. Our next step is to design a therapeutic delivery vehicle to designate microRNA-765 specifically to PCa cells and inhibit tumorigenic functions. To achieve this, microRNA-765 will be linked to a PCa targeting RNA aptamer, which recognizes prostate specific membrane antigen highly expressed in most castration-resistant or metastatic PCa cells. Antitumor-specific tissue targeting of this PSMA aptamer-linked microRNA will be investigated in both cell and xenograft animal models. This novel PCa-specific therapy is expected to be more stable due to the 2 Fluoropyrimidine incorporation, non-immunogenic due to the 2 Fluoropyrimidine, and the small RNA structure (<120 bases), and have less off-target cytotoxicity because of the presence of specific cancer-targeting components. Findings from this study will reveal the tumor-suppressing effect of microRNA-765 during PCa cell growth and metastasis through silencing expression of multiple oncogenes. The mechanism involved in miR-765 s downstream effects and target miRNA will be identified. More importantly, the proposed innovative design of a PCa-specific microRNA therapy will revolutionize RNA therapeutic strategies for treating malignant PCa. It is hormone-independent, making it capable to target both early prostate disease cells that are androgen-dependent and later malignant PCa cells that may have acquired androgen resistance. This design also helps strategize tailor-made therapies for
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510496
Entities
People
- Ana Cheong
Organizations
- United States Army
- University of Cincinnati