Julian William, Sergeeva Olga, Cao Wei, Wu Chunying, Erokwu Bernadette, Flask Chris, Zhang Lifang, Wang Xinning, Basilion James, Yang Sichun, Lee Zhenghong
Radiology Department, Case Western Reserve University, Cleveland, Ohio, USA.
Biomedical Engineering Department, Case Western Reserve University, Cleveland, Ohio, USA.
Cancer Biother Radiopharm. 2024 Dec;39(10):721-732. doi: 10.1089/cbr.2024.0066. Epub 2024 Sep 13.
Prostate specific membrane antigen (PSMA)-targeted radioligand therapies represent a highly effective treatment for metastatic prostate cancer. However, high and sustain uptake of PSMA-ligands in the salivary glands led to dose limiting dry mouth (xerostomia), especially with α-emitters. The expression of PSMA and histologic analysis couldn't directly explain the toxicity, suggesting a potential off-target mediator for uptake. In this study, we searched for possible off-target non-PSMA protein(s) in the salivary glands. A machine-learning based quantitative structure activity relationship (QSAR) model was built for seeking the possible off-target(s). The resulting target candidates from the model prediction were subjected to further analysis for salivary protein expression and structural homology at key regions required for PSMA-ligand binding. Furthermore, cellular binding assays were performed utilizing multiple cell lines with high expression of the candidate proteins and low expression of PSMA. Finally, PSMA knockout (PSMA-/-) mice were scanned by small animal PET/MR using [Ga]Ga-PSMA-11 for in-vivo validation. The screening of the trained QSAR model did not yield a solid off-target protein, which was corroborated in part by cellular binding assays. Imaging using PSMA-/- mice further demonstrated markedly reduced PSMA-radioligand uptake in the salivary glands. Uptake of the PSMA-targeted radioligands in the salivary glands remains primarily PSMA-mediated. Further investigations are needed to illustrate a seemingly different process of uptake and retention in the salivary glands than that in prostate cancer.
前列腺特异性膜抗原（PSMA）靶向放射性配体疗法是转移性前列腺癌的一种高效治疗方法。然而，唾液腺中PSMA配体的高摄取和持续摄取导致了剂量限制性口干（口腔干燥症），尤其是使用α发射体时。PSMA的表达和组织学分析无法直接解释这种毒性，这表明存在一种潜在的非靶向摄取介质。在本研究中，我们在唾液腺中寻找可能的非靶向非PSMA蛋白。构建了基于机器学习的定量构效关系（QSAR）模型来寻找可能的非靶向蛋白。对模型预测得到的候选靶点进行进一步分析，以研究唾液蛋白表达以及PSMA配体结合所需关键区域的结构同源性。此外，利用多种候选蛋白高表达而PSMA低表达的细胞系进行细胞结合试验。最后，使用[Ga]Ga-PSMA-11对PSMA基因敲除（PSMA-/-）小鼠进行小动物PET/MR扫描以进行体内验证。训练后的QSAR模型筛选未产生可靠的非靶向蛋白，细胞结合试验部分证实了这一点。使用PSMA-/-小鼠成像进一步表明唾液腺中PSMA放射性配体的摄取明显减少。唾液腺中PSMA靶向放射性配体的摄取主要仍由PSMA介导。需要进一步研究来说明唾液腺中摄取和保留过程与前列腺癌中看似不同的过程。
