Abstract 4698: Towards treating prostate cancer using an engineered sodium/iodide symporter (NIS) protein

Abstract The sodium/iodide symporter (NIS) is the theranostic plasma membrane protein that mediates the active transport of iodide (I-) ions and various clinically approved radiotracers used for imaging [such as pertechnetate (99mTcO4 -), radioiodide (123I-), and tetrafluoroborate ([18F]BF4 -)] and for therapeutic purposes [e.g., radioiodide (131I-) and preclinically approved perrhenate (186/188ReO4 -)]. For over 80 years, targeted internal radiation therapy (TIRT) has been used successfully to treat thyroid cancer: administered 131I- is selectively accumulated in the thyroid cancer cells by NIS. NIS-mediated TIRT is a promising approach to treating prostate cancer, the second deadliest cancer in men in the United States and Europe. About 1 in 7 men will be diagnosed with prostate cancer at some point in their life. Currently available therapies, including prostate surgery and targeted irradiation are often ineffective against advanced/recurrent and metastatic prostate cancer, so new treatments are urgently needed. In order for NIS-based TIRT to be successful, three challenges must be overcome: a) the thyroid must be protected from β-radiation; b) the immune response triggered by the viral vectors used for NIS delivery must be mitigated; and c) tissue specificity must be ensured. To tackle these challenges, we have engineered a NIS protein (PF-NIS) by replacing two amino acids that are close to the substrate cavity (the substitutions are L253P and V254F). PF-NIS differentiates between two substrates, namely I- and oxyanions (such as 186ReO4 - and 99mTcO4-): it transports oxyanions but virtually no I-. We have shown in in vitro experiments that cells expressing wild-type NIS (WT NIS) do not die when treated with 186ReO4 - and saturating concentrations of non-radioactive iodide (I-) (100 μM), because WT NIS does not transport oxyanions in the presence of excess I-. To decrease immunogenicity, we will use polyplexes which are nanocomplexes composed of DNA and polyvalent molecules such as polyethyleneimine (PEI). Polyplexes were formed using in vivo jetPEI and PF-NIS cDNA at an N/P ratio of 1:8. Dynamic light scattering analysis revealed an average polyplex size of approximately 100 nm. Morphological analysis using scanning electron microscopy and atomic force microscopy confirmed that the polyplexes were spherical. Tissue specificity was achieved by suing the prostate-specific antigen (PSA) promoter, a well-characterized regulatory element that drives gene expression specifically in prostate epithelial cells and is highly active in prostate cancer cells. We conclude that polyplexes containing the PF-NIS cDNA under the PSA promoter will render prostate cancer cells susceptible to being treated with 186/188ReO4 - even in the presence of non-radioactive I-, which will protect the thyroid. Citation Format: Haswitha Sabbineni, Alejandro Llorente, Todd D Giorgio, Nancy Carrasco. Towards treating prostate cancer using an engineered sodium/iodide symporter (NIS) protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4698.