Fibroblast activation protein and focal adhesion kinase: novel stromal therapeutic targets in pancreatic adenocarcinoma

Abstract

4094 Background: Fibroblast activation protein (FAP) is a serine protease expressed on tumor stromal fibroblasts which results in tumor growth potentiation. Focal adhesion kinase (FAK) is a protein tyrosine kinase which promotes cell growth and migration through the extracellular matrix. Given the extensive desmoplasia characteristic of pancreatic adenocarcinoma, we hypothesized that FAP and FAK would be overexpressed in pancreatic cancer and contribute to poor outcome. Methods: Twenty-nine paraffin-embedded pancreatic adenocarcinoma specimens from patients undergoing curative resection were obtained from the Fox Chase Cancer Center tumor bank. Four samples (2 normal and 2 mucinous borderline tumors) served as controls. FAP and FAK expression was assessed by immunohistochemistry and graded by staining extent (%) and intensity (0–3+). Results: Ninety percent of tumor specimens (26/29) expressed FAP in either fibroblasts surrounding tumor (FST), surrounding stroma (SS), or tumor. The highest expression level by intensity was: 3+ (14), 2+ (9), 1+ (3). A strong correlation was noted between FAP expression in FST and in SS (Pearson correlation coefficient 0.75, p<0.001). In contrast, control samples displayed no FAP expression in SS. FAK was expressed on tumor cells in all 29 samples, with three-quarters having 100% staining. In addition, median FAK expression in SS was 50%. A strong correlation was noted between percent staining of FAP and FAK in SS (Pearson correlation coefficient 0.637 (p<0.001). Conclusions: FAP is overexpressed in 90% of pancreatic adenocarcinoma specimens, with similar expression in both FST and SS. FAK is also overexpressed in SS and correlates with expression of FAP, suggesting that interaction between these proteins may contribute to pancreatic cancer invasiveness. Additional samples are being evaluated and correlation with clinical characteristics is ongoing. As targeting of FAP appears promising in preclinical models, pancreatic cancer is an excellent disease for future clinical development of stromal-directed therapeutics. No significant financial relationships to disclose.