Abstract PO-129: Using the castration resistant prostate cancer patient-derived xenograft (PDX) tumor model to identify mRNA/miRNA biomarkers which distinguish abiraterone treatment responders and non-responders
Authors: Ouyang Bin , Song Dan , Biesiada Jacek , Ren Yan , Medvedovic Mario , Tarapore Pheruza 
Published: December 2020

Prostate cancer (PCa) is the most frequent cancer occurring in men in the United States and is the second leading cause of cancer deaths in men. Median survival for patients with metastatic hormone refractory PCa (HRPC/CRPC) is around 18 months. Abiraterone (Abi) is a next-generation androgen receptor targeting agent which has significant effects on PCa patients' survival, and has been approved for treatment of metastatic and CRPC. However, it is clear that there is development of Abi resistance (Abi-R). Abi inhibits the steroidogenic enzyme CYP17A1, a critical enzyme in androgen biosynthesis in the adrenals, testis as well as tumor tissues. To screen and identify biomarkers (genes and microRNA (miRNA)) for Abi-R in a heterogenous tumor, we used patient derived PCa xenograft animal model (PCa-PDX mice). Recent advances in the development of PDX models and their increasing sophistication have led to their escalating use for anticancer drug research and development, and as predictive clinical models. Hence, for the correct identification of Abi-R markers, we proposed using PCa-PDX animal model (PDX mice). We hypothesized that changes in miRNA expression underlie Abi resistance (Abi-R) mechanisms. Each tumor bearing mouse was castrated resulting in tumor regression followed by regrowth/relapse phase. Mice were then treated with Abi. The tumors were collected either once they regressed (called CRABS), or reinoculated into castrated host if they showed continued growth. The new host was treated with Abi once tumors reached 50-300 mm3. Tumors were harvested when they reached a volume of ~600-800 mm3 (CRABR2). The RNA was extracted from tumors using the miRvana kits, and RNA/miRNA-seq performed. We compared the Abi sensitive vs the Abi resistant (CRABR2) groups, to identify 316 genes and 55 miRNA whose expression was significantly changed between these two groups. We used Venn diagrams to overlap the validated gene targets for the miRNA (5,557 genes) with our 316 gene dataset. 85 common genes were identified, of which 63 genes were validated targets of hsa-miR-335 (1.7 fold in CRABS vs CRABR2), and 8 genes were validated targets of hsa-miR-574 (0.4 fold in CRABS vs CRABR2). Hsa-miR-335 has been previously identified to function as a candidate tumor suppressor in PCa. Reduced expression of miR-335 was found in human PCa tissues comparing with paired adjacent benign prostate tissues (P &lt; 0.05). Moreover, the increased expression of miR-335 suppressed cell proliferation, invasion and migration of PCa cell lines in vitro. It has been found to suppress bone metastasis in PCa via targeting endothelial nitric oxide synthase. MicroRNA-574-5p promotes metastasis of non-small cell lung cancer, triple negative breast cancer and colorectal cancer to name a few. However, their function in Abi resistance has not been explored. In conclusion, we have identified two promising miRNA for distinguishing Abi sensitive from resistant tumors whose targeting should have profound effects on sensitizing castration resistant tumors to Abi.

Citation Format: Bin Ouyang, Dan Song, Jacek Biesiada, Yan Ren, Mario Medvedovic, Pheruza Tarapore. Using the castration resistant prostate cancer patient-derived xenograft (PDX) tumor model to identify mRNA/miRNA biomarkers which distinguish abiraterone treatment responders and non-responders [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-129.