Abstract
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.
Keywords:
antibody‐payload conjugates; cell surface proteins; chemoresistance; confocal microscopy; epidermal growth factor receptor; epithelial cell adhesion molecule; flow cytometry; folate receptor alpha (FOLR1); high‐grade serous ovarian cancer; integrin alpha 5 (ITGA5/CD49e); integrin beta 5 (ITGB5); internalization; low‐density lipoprotein receptor‐related protein 1 (LRP1/CD91); mRNA sequencing; personalized treatment; primary cancer cell lines; proteomics; receptor‐mediated endocytosis; transferrin receptor protein 1 (TFRC/TfR1/CD71); tumor heterogeneity; tumor‐targeted activatable photoimmunotherapy.