Towards treating prostate cancer with 188 ReO 4 - using an engineered human sodium/iodide symporter (NIS) protein

The sodium/iodide symporter (NIS) is the plasma membrane protein that mediates the active transport of iodide (I - ) and various clinically approved radiotracers used for imaging [such as pertechnetate ( 99m TcO 4 - ), radioiodide ( 123 I - ), and tetrafluoroborate ([ 18 F] BF 4 - )] and for therapeutic purposes [e.g., 131 I - and preclinically approved perrhenate ( 186/188 ReO 4 - )]. For over 80 years, targeted internal radiation therapy (TIRT) has been used successfully to treat thyroid cancer: administered radioactive iodide ( 131 I - ) 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 8 men will be diagnosed with prostate cancer at some point in their life. Localized prostate cancer is typically treated with prostatectomy or definitive radiotherapy (RT), but these treatments fail to cure up to 20-40% of patients. For metastatic castration-resistant prostate cancer (mCRPC), there are only a very limited number of effective agents available with unique mechanisms: androgen receptor antagonists, inhibitors of androgen synthesis, cytotoxic chemotherapy, immune-cell transfer therapy, and bone-directed and prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals, all of which improve survival only modestly , by ~4 months, in randomized trials for patients with mCRPC. In order for NIS-based TIRT to be successful, three challenges must be overcome: (i) thyroid protection from beta-radiation, (ii) immune response mitigation, and (iii) tissue specificity. To overcome these limitations, we engineered a NIS molecule with 2 amino acid substitutions L253P and V254F: PF-NIS. PF-NIS selectively transport oxyanions but does not transport I - . In vitro studies demonstrated that PF-NIS-expressing cells were selectively susceptible to 186 ReO 4 - + 100 µM I - in contrast to WT-NIS cells, which survived in the presence of 100 µM I - . To minimize immunogenicity, PF-NIS cDNA was delivered via polyplexes ( in vivo jetPEI), and tissue specificity was ensured by the prostate-specific antigen (PSA) promoter. Building on these data, athymic nude mice with PF-NIS-bearing tumors were imaged by SPECT-CT, which revealed PF-NIS-mediated tracer accumulation in tumors after intratumoral or intravenous delivery of PF-NIS polyplexes, as well as an ~80% decrease in thyroidal signal following administration of 100 µM I⁻. Treatment with 188 ReO 4 - markedly reduced tumor volume while the thyroids of the mice were protected, leveraging the higher energy and shorter half-life of 188 Re vis-à-vis those of 186 Re or 177 Lu (the radionuclide currently used in most PSMA targeted radiopharmaceuticals). This approach constitutes a novel strategy for NIS-based TIRT, selectively targeting prostate cancer cells while protecting the thyroid.