Correlation of circulating IL-8 levels with improved overall survival in advanced pancreatic cancer patients in response to antisense OT-101 (trabedersen) therapy.

Abstract

444 Background: Overexpression of the transforming growth factor-beta 2 (TGF-β2) has been suggested as a pivotal factor for malignant progression of pancreatic cancer (PAC). OT-101 (Trabedersen) is a phosphorothioate antisense oligodeoxynucleotide target the human TGF-β2 mRNA. A Phase I/II study of OT-101 was characterized by outstanding overall survival (OS) in patients with advanced PAC. In this study, we examined the association between plasma levels of 31 cyto-/chemokines and OS outcomes in PAC patients treated with OT-101. Methods: Plasma levels of 31 cyto-/chemokine were tracked over a period of 11 days at 8 time points during 3 cycles of intravenous OT-101 therapy (140 mg/m2/day) for 12 PAC patients. A mixed ANCOVA model was developed to time evolution of 19 cyto-/chemokine levels with median expression 1 following OT-101 therapy. Pearson pairwise correlation coefficients of cyto-/chemokine levels across all time points and all patients were utilized to construct a correlation cluster to identify co-regulated cyto-/chemokines. Regression and hierarchical cluster analyses were performed to identify potential cytokine signatures. Protein-protein interaction networks were constructed using STRING10 algorithm. Plasma cyto-/chemokine levels were compared with OS outcome. Results: Three highly correlated subsets of cyto-/chemokines (Cluster 1: EGF, MIP-1α, MIP-1b; Cluster 2: FGF-2, IL-1R, MIG, IP-10, IL-15, IFN-α, IL-12A; Cluster 3: IL-2R, IL-6, IL-8, HGF) were identified following OT-101 therapy. An increasing trend was observed among 13 cytokines. 4 of the 12 patients exhibited a consistent increase in MIP-1α and IL-1b. Suppression of TGF-b signaling by OT-101 led to upregulation of IL-15, IP-10 and HGF. 3 significant associations of cyto-/chemokine and OS were observed at Cycle 1 measurements. The ANCOVA model that examined the levels of 31 cyto-/chemokines with OS as the co-variate resulted in IL-8 exhibiting a significant positive association with OS ( P= 0.0039). Conclusions: Levels of IL-8 were positively associated with OS across 12 PAC patients serving as potential biomarkers for treatment outcome following OT-101 therapy. Clinical trial information: NCT00844064.