Abouzayed Ayman, Zedan Wahed, Altai Mohamed, Strand Joanna, Örbom Anders
Department of Medicinal Chemistry, Uppsala University Uppsala, Sweden.
Department of Oncology, Lund University Lund, Sweden.
Am J Nucl Med Mol Imaging. 2023 Jun 25;13(3):107-117. eCollection 2023.
One novel option for treating metastatic castration resistant prostate cancer is radionuclide therapy targeting prostate-specific membrane antigen (PSMA), e.g. [Lu]Lu-PSMA-617. Overexpression of HER2 has been found in 80% of metastatic cases of prostate cancer. Previous research showed that HER2 is elevated post irradiation in PC-3 prostate cancer cells. Co-treating with anti-HER2 antibody Trastuzumab gave less proliferation of irradiated tumor cells in vitro, and when using radionuclide therapy, also in vivo. The aim of this study is to determine whether the same holds true in PSMA-expressing PC-3 PIP cells using [Lu]Lu-PSMA-617 radionuclide therapy. PC-3 PIP and 22Rv1 prostate cancer cells were tested in vitro, treated with 6 Gy of x-rays with or without Trastuzumab incubation. We measured uptake of HER2-targeting affibody [Ga]Ga-ABY-025 and cell survival, e.g. using the WST-1 assay. Three groups (n=10 each) of male nude Balb/c mice were inoculated with PC-3 PIP xenograft tumors and treated with just [Lu]Lu-PSMA-617 (20 MBq), [Lu]Lu-PSMA-617 (20 MBq) and Trastuzumab (4 × 5 mg/kg), or left untreated. Tumor sizes and animal survival was observed. In vitro, x-ray irradiation did reduce survival in 22Rv1 but not PC-3 PIP cells, and there was no significant effect of Trastuzumab treatment. Cells expressed HER2 but not significantly elevated post irradiation. In vivo, mice co-treated with Trastuzumab had significantly longer survival than untreated mice, but not than only [Lu]Lu-PSMA-617. Staining of tumor sections showed similar HER2 and PSMA expression across groups. In conclusion, these results give no support for any benefit from co-treatment with anti-HER2 antibody for PSMA-targeted radioligand therapy.
治疗转移性去势抵抗性前列腺癌的一种新选择是靶向前列腺特异性膜抗原（PSMA）的放射性核素疗法，例如[镥]镥-PSMA-617。在80%的前列腺癌转移病例中发现了HER2的过表达。先前的研究表明，在PC-3前列腺癌细胞中，照射后HER2水平会升高。与抗HER2抗体曲妥珠单抗联合治疗在体外可使照射后的肿瘤细胞增殖减少，在使用放射性核素疗法时，在体内也有同样效果。本研究的目的是确定在使用[镥]镥-PSMA-617放射性核素疗法的PSMA表达阳性的PC-3 PIP细胞中是否也是如此。对PC-3 PIP和22Rv1前列腺癌细胞进行体外测试，用6 Gy的X射线进行照射，同时或不同时孵育曲妥珠单抗。我们测量了靶向HER2的亲和体[镓]镓-ABY-025的摄取以及细胞存活率，例如使用WST-1检测法。将三组（每组n = 10）雄性裸Balb/c小鼠接种PC-3 PIP异种移植肿瘤，并分别用[镥]镥-PSMA-617（20 MBq）、[镥]镥-PSMA-617（20 MBq）和曲妥珠单抗（4×5 mg/kg）进行治疗，或不进行治疗。观察肿瘤大小和动物存活率。在体外，X射线照射确实降低了22Rv1细胞的存活率，但对PC-3 PIP细胞没有影响，曲妥珠单抗治疗也没有显著效果。细胞表达HER2，但照射后没有显著升高。在体内，与曲妥珠单抗联合治疗的小鼠存活率明显长于未治疗的小鼠，但不比仅使用[镥]镥-PSMA-617治疗的小鼠长。肿瘤切片染色显示各组之间HER2和PSMA表达相似。总之，这些结果不支持抗HER2抗体与PSMA靶向放射性配体疗法联合治疗有任何益处。
