Timilsina Sudip, Amara Anish Raju, Abu Rafay, Spring Bryan Q
Department of Physics, Northeastern University, Boston, Massachusetts, USA.
Translational Biophotonics Cluster, Northeastern University, Boston, Massachusetts, USA.
Photochem Photobiol. 2025 Apr 9. doi: 10.1111/php.14091.
Tumor-targeted, activatable photoimmunotherapy (taPIT) has shown promise in preclinical models to selectively eliminate drug-resistant micrometastases that evade standard treatments. Moreover, taPIT has the potential to resensitize chemo-resistant tumor cells to chemotherapy, making it a complementary modality for treating recurrent high-grade serous ovarian cancer (HGSOC). However, the established implementation of taPIT relies on the overexpression of EGFR in tumor cells, which is not universally observed in HGSOCs. Motivated by the need to expand taPIT applications beyond EGFR, we conducted mRNA-sequencing and proteomics to identify alternative cell surface targets for taPIT in patient-derived HGSOC cell cultures with weak EGFR expression and lacking expression of other cell surface proteins commonly reported in the literature as overexpressed in ovarian cancers, such as FOLR1 and EpCAM. Our findings highlight TFRC and LRP1 as promising alternative targets. Notably, TFRC was overexpressed in 100% (N = 5) of the patient-derived HGSOC models tested, whereas only 60% of models had high EpCAM expression, suggesting that future larger cohort studies should include TFRC. While this study focuses on target identification, future work will expand the approaches developed here to larger HGSOC biopsy repositories and will also develop and evaluate antibody-photosensitizer conjugates targeting these proteins for taPIT applications.
肿瘤靶向可激活光免疫疗法（taPIT）在临床前模型中已显示出有选择性消除逃避标准治疗的耐药微转移灶的潜力。此外，taPIT有可能使化疗耐药的肿瘤细胞对化疗重新敏感，使其成为治疗复发性高级别浆液性卵巢癌（HGSOC）的一种补充方式。然而，已确立的taPIT实施依赖于肿瘤细胞中表皮生长因子受体（EGFR）的过表达，而在HGSOC中并非普遍观察到这种情况。出于将taPIT应用扩展到EGFR以外的需求，我们进行了mRNA测序和蛋白质组学研究，以在EGFR表达较弱且缺乏文献中通常报道的在卵巢癌中过表达的其他细胞表面蛋白（如叶酸受体1（FOLR1）和上皮细胞黏附分子（EpCAM））表达的患者来源的HGSOC细胞培养物中鉴定taPIT的替代细胞表面靶点。我们的研究结果突出了转铁蛋白受体（TFRC）和低密度脂蛋白受体相关蛋白1（LRP1）作为有前景的替代靶点。值得注意的是，在所测试的100%（N = 5）患者来源的HGSOC模型中转铁蛋白受体过表达，而只有60%的模型有高上皮细胞黏附分子表达，这表明未来更大规模的队列研究应纳入转铁蛋白受体。虽然本研究侧重于靶点鉴定，但未来的工作将把这里开发的方法扩展到更大的HGSOC活检样本库，还将开发和评估针对这些蛋白的抗体 - 光敏剂偶联物用于taPIT应用。
