Abstract 5039: Development of a prostate cancer PDX model radioresistant to PSMA targeted radionuclide therapy
Authors: Thaysen Maria , Christensen Esben , Nielsen Rikke N. , Wick Michael , Wessel Mette M. , Kristensen Lotte K. , Gnosa Sebastian , Nielsen Carsten H. 
Published: April 2023

Abstract
Prostate cancer is the second most common cancer diagnosis worldwide and the fifth leading cause of cancer related death among men. Lutetium Lu 177 vivivotide tetraxetetan was recently approved by the FDA for treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. However, not all patients respond to treatment and combination therapies may improve outcomes. One approach is to combine targeted radionuclide therapy with inhibitors targeting DNA damage response pathways such as ATM/ATR inhibitors to enhance the radiosensitivity of the cancer cells. Currently, models used 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 aimed at developing a radioresistant PSMA positive prostate cancer patient-derived xenograft (PDX) model based on the ST1273 model (XenoSTART). ST1273 originates from a sixty-five-year-old Hispanic male that did not receive treatment prior to sampling. The model is characterized by overexpression of androgen receptor and PSMA. Tumors were implanted in nude mice and radioresistance was induced by external beam radiation therapy (3 × 2Gy per cycle) until tumor growth was unresponsive to the treatment. Flow cytometry were applied to evaluate if altered proliferation rate or changes in the tumor microenvironment (TME) convers the resistance.
Out of five initially treated tumors, one tumor re-occurred after 19 days. Repeating the treatment led to an initial decrease in tumor volume but the growth delay was reduced to 12 days. A third treatment rendered the tumor resistant as tumor growth was unaffected. Current evidence confirms that radioresistance was maintained when passaging, and PSMA expression was unaffected. Next, we tested whether the tumor would also withstand targeted radionuclide therapy. Animals implanted with parental or radioresistant ST1273 tumors were treated with Lu177-PSMA-617 (5MBq, QW x2). The treatment reduced tumor size in both tumor types, but significantly less in the resistant model. Moreover, parental tumors had a significantly slower recurrence of 45 days compared to the resistant tumors that relapsed 24 days after the first dosing. Flow cytometry analysis of control and treated tumors (parental and radioresistant) showed that the radioresistance might be attributed to alterations in the cell cycle control.
Altogether, we developed a PDX prostate cancer model that is resistance to external beam radiation and PSMA targeted radionuclide therapy. This model will allow us to further characterize radioresistance and evaluate combinatorial therapy in a clinically relevant model.
Citation Format: Maria Thaysen, Esben Christensen, Rikke N. Nielsen, Michael Wick, Mette M. Wessel, Lotte K. Kristensen, Sebastian Gnosa, Carsten H. Nielsen. Development of a prostate cancer PDX model radioresistant to PSMA targeted radionuclide therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5039.