Predicting Response to Neoadjuvant Therapy in Oesophageal Adenocarcinoma.

(1) Background: Oesophageal cancers are often late-presenting and have a poor 5-year survival rate. The standard treatment of oesophageal adenocarcinomas involves neoadjuvant chemotherapy with or without radiotherapy followed by surgery. However, less than one third of patients respond to neoadjuvant therapy, thereby unnecessarily exposing patients to toxicity and deconditioning. Hence, there is an urgent need for biomarkers to predict response to neoadjuvant therapy. This review explores the current biomarker landscape. (2) Methods: MEDLINE, EMBASE and ClinicalTrial databases were searched with key words relating to "predictive biomarker", "neoadjuvant therapy" and "oesophageal adenocarcinoma" and screened as per the inclusion and exclusion criteria. All peer-reviewed full-text articles and conference abstracts were included. (3) Results: The search yielded 548 results of which 71 full-texts, conference abstracts and clinical trials were eligible for review. A total of 242 duplicates were removed, 191 articles were screened out, and 44 articles were excluded. (4) Discussion: Biomarkers were discussed in seven categories including imaging, epigenetic, genetic, protein, immunologic, blood and serum-based with remaining studies grouped in a miscellaneous category. (5) Conclusion: Although promising markers and novel methods have emerged, current biomarkers lack sufficient evidence to support clinical application. Novel approaches have been recommended to assess predictive potential more efficiently.

EpCAM-Binding DARPins for Targeted Photodynamic Therapy of Ovarian Cancer.

Ovarian cancer is the most lethal gynecological malignancy due to late detection associated with dissemination throughout the abdominal cavity. Targeted photodynamic therapy (tPDT) aimed at epithelial cell adhesion molecule (EpCAM), overexpressed in over 90% of ovarian cancer metastatic lesions, is a promising novel therapeutic modality. Here, we tested the specificity and activity of conjugates of EpCAM-directed designed ankyrin repeat proteins (DARPins) with the photosensitizer IRDye 700DX in in vitro and in vivo ovarian cancer models. EpCAM-binding DARPins (Ec1: Kd = 68 pM; Ac2: Kd = 130 nM) and a control DARPin were site-specifically functionalized with fluorophores or IRDye 700DX. Conjugation of anti-EpCAM DARPins with fluorophores maintained EpCAM-specific binding in cell lines and patient-derived ovarian cancer explants. Penetration of DARPin Ec1 into tumor spheroids was slower than that of Ac2, indicative of a binding site barrier effect for Ec1. DARPin-IRDye 700DX conjugates killed EpCAM-expressing cells in a highly specific and illumination-dependent fashion in 2D and 3D cultures. Furthermore, they effectively homed to EpCAM-expressing subcutaneous OV90 xenografts in mice. In conclusion, the high activity and specificity observed in preclinical ovarian cancer models, combined with a high specificity in patient material, warrant a further investigation of EpCAM-targeted PDT for ovarian cancer.