Abstract 702: Development of a radioresistant PDX prostate cancer model to evaluate potential radiosensitizing compounds

Abstract Prostate cancer is the second most common cancer diagnosis worldwide and the fifth leading cause of cancer related death among men. Several treatment strategies are used including the FDA approved 177Lu-vipivotide tetraxetan (177Lu-PSMA-617) for the treatment of prostate-specific membrane antigen (PSMA) -positive metastatic castration-resistant prostate cancer. However, not all patients respond to treatment due to tumor intrinsic resistance mechanisms. Therefore, the combination of targeted radionuclide therapy with inhibitors against e. g. DNA damage response, cell cycle progression or cell survival pathways are investigated to enhance the radiosensitivity of the tumor. Current models to study radioresistance in prostate cancer are based on cancer cell lines or cell-line derived xenograft models, but these models do not account for the heterogenous and complex biology of the disease. To overcome this issue, we have developed a radioresistant patient-derived xenograft (PDX) prostate cancer model (ST1273, XenoSTART), that is positive for PSMA. Resistance to radiation was initially established by sequential irradiation of the tumors with external beam radiation. Moreover, the model has proven to be resistant towards treatment with 30 MBq 177Lu-PSMA-617. Utilizing this radioresistant model we are now able to investigate the treatment response of 177Lu-PSMA-617 in combination with different drug inhibitor classes to evaluate their potential radiosensitizing effect. The PARP inhibitor, Olaparib, was administered at 50 mg/kg QDx48 alone or in combination with a single dose of 177Lu-PSMA-617 in radioresistant ST1273 tumor bearing NMRI nude mice. First results showed a prolonging treatment effect of Olaparib given in combination with 177Lu-PSMA-617 compared to 177Lu-PSMA-617 alone. Tumor relapse was observed 29 days after treatment with 177Lu-PSMA-617 alone, whereas it was observed 49 days after combination treatment. Olaparib given alone did not influence tumor growth. To further investigate the mechanism of resistance we are currently investigating the radiosensitizing potential of additional compounds and evaluating the tumors by RNA- and whole-exome- sequencing. Altogether, we successfully established a PSMA positive prostate cancer model resistant to PSMA targeted radionuclide therapy. With this model we are able to investigate the radiosensitizing effect of different drug classes. Citation Format: Maria Zeiler Alfsen, Maria Thaysen, Nikoline Nielsen, Michael Wick, Luke Piggott, Sebastian Gnosa, Carsten Haagen Nielsen. Development of a radioresistant PDX prostate cancer model to evaluate potential radiosensitizing compounds abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 702.