microRNA Biomarkers to Generate Sensitivity to Abiraterone-Resistant Prostate Cancer
Abstract
Prostate cancer (PCa) is the most frequent cancer occurring in men in the United States, and, in men, is the second leading cause of cancer deaths, after lung cancer. While prostate-specific antigen screening has dramatically improved early detection of this disease, PCa is still the second leading cause of cancer deaths in men. A substantial proportion of patients develop an incurable disseminated disease after local therapy, even if the primary lesion appears localized to the prostate gland when first diagnosed. Also, a large number of advanced PCas become androgen-independent, for which there is no known cure. Indeed, median survival for patients with metastatic hormone refractory PCa is still around 18 months. Thus, there is an urgent need to come up with new treatment regimens for these patients. Clinical trials with Abiraterone (Abi) showed significant effects on castration-resistant PCa (CRPC) patients survival. This led to Food and Drug Administration approval of Abi (2011). However, ultimately, there is development of resistance to Abi (Abi-R). The identification of Abi-R markers is important for designing therapeutic interventions sensitizing PCas to combination Abi therapies, and for prognostic applications to monitor and predict for disease relapse. Abi inhibits CYP17A1, a critical enzyme in androgen biosynthesis. Since Abi targets CYP17A1 in the adrenals as well as has direct effects on PCas, an in vitro approach to identify biomarkers of resistance to Abi can be imprecise. We therefore propose to use patient derived PCa xenograft animal model (PCa-PDX mice) to identify differently expressed microRNA (miRNA) on Abi treatment. Additionally, we will develop a combination therapeutic approach to treat PCa, employing Abi plus RNA therapy, as a promising methodological approach. A candidate cell surface receptor is PSMA (prostate specific membrane antigen). PSMA expression is associated with higher Gleason scores in tumors, and with increased aneuploidy. It is currently used as a tumor marker for diagnosis, monitoring, and prognosis of prostatic carcinoma. Elevated levels of PSMA are also used as an independent marker for predicting disease relapse. We will use an RNA aptamer which binds specifically to PCa cells to deliver the miRNA. miRNA have an advantage over siRNA for gene silencing since they can target multiple components of the cellular networks/signaling pathways responsible for advanced disease progression. Our central hypothesis is that changes in miRNA expression underlie Abi-R mechanisms and that PCa-PDX mice will be excellent surrogates to identify markers for Abi-R. We further postulate that RNA therapy (restoring or targeting miRNA) should increase sensitivity of Abi-R tumors, allowing us to prolong treatments, and hence the life of a patient. However, the challenge lies in delivering the therapeutic RNA(s) to the PCa in a highly specific, efficient, non-pathogenic and non-degraded form. Our study addresses this issue. Our objectives are: (1) To identify microRNA responsible for Abi-R, using PCa-PDX mice that maintain the tissue architecture and molecular signature of the primary tumor. (2) To devise a highly potent and PCa-specific therapy consisting of a therapeutic delivery vehicle (TDV) that consists of a pre-microRNA or mature RNA and a RNA aptamer that recognizes PCa cells, designed as two separate RNA strands with complementary ends, which can bind to each other and form a complex. The TDV should enter PSMA-expressing malignant cells in a highly efficient and specific manner. Moreover, the use of 2 Fluoro pyrimidine RNA makes the RNA stable and avoids problems of immune response and rejection of protein vectors after repeated long-term systemic drug administration. The small size of the RNA molecules make them easy to generate and the transition to large-scale amounts of RNA needed for use in clinical studies should be fast and easy. (3) To gain insights rega
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510353
Entities
People
- Pheruza Tarapore
Organizations
- United States Army
- University of Cincinnati