Abstract 3537: Stem-cell based selective delivery of alpha keto reductases for therapeutic targeting of residual androgens in prostate cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 75; no. 15_Supplement; p. 3537
• Main Authors: Ranjan, Manish, Abd Elmageed, Zakaria, Kim, Hogyoung, Datta, Amrita, Bhasin, Nobel, Braun, Steven E., Mondal, Debasis, Abdel-Mageed, Asim B.
• Format: Journal Article
• Language: English
• Published: 01.08.2015
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2015-3537

Abstract The twice as high incidence and mortality among African Americans (AA) compared to Caucasian Americans and other ethnic minorities remains elusive. The de novo synthesis of androgens by prostate tumors provides a significant survival advantage leading to outgrowth of castration resistant tumors. The “intracrine” production of androgens in the tumor microenvironment is greatly influenced by the synthesis of androgen metabolizing enzymes (AMEs) and the level of circulating hormones. Currently, targeting de novo synthesis of androgens in tumor microenvironment is singularly the toughest challenge presented to oncologists. Our present research attempts to identify and exploit the key players among the AMEs for targeting the backdoor pathway of DHT synthesis in castration resistant prostate cancer (CRPC). Comparative analysis of gene expression of AMEs in microdissected cells versus the adjacent normal tissue revealed AKR1C4 to be the most promising candidate for targeting the backdoor pathway in DHT synthesis. Existing literature supports this view since Type 1 3a-HSD enzyme has been shown to readily oxidize testosterone to Δ4-androstene-3, 17-dione in a substrate dependent reaction. Our analysis using recombinant AKR1C4 induced cytotoxicity and apoptosis in androgen dependent PC cells in vitro. Next, using a lentivirus construct, we genetically engineered tumor-tropic adipose-derived stem cells (ASCs) to express and secreted AKR1C14 (mouse homolog of AKR1C4). The results showed that ASCs are capable of expressing the enzyme, which can catabolize DHT in vitro and induce apoptosis in androgen dependent prostate cancer cells as shown by DHT Elisa, psPSA reporter assays and cytotoxicity and survival assays. Our current research plan is to examine the efficacy of tumor-tropic AKR1C14-expressing ASCs in targeting and inhibiting prostate metastatic growth in an animal model system. Citation Format: Manish Ranjan, Zakaria Abd Elmageed, Hogyoung Kim, Amrita Datta, Nobel Bhasin, Steven E. Braun, Debasis Mondal, Asim B. Abdel-Mageed. Stem-cell based selective delivery of alpha keto reductases for therapeutic targeting of residual androgens in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3537. doi:10.1158/1538-7445.AM2015-3537