Impact of targeting transforming growth factor β-2 with antisense OT-101 on the cytokine and chemokine profile in patients with advanced pancreatic cancer
Authors D'Cruz OJ, Qazi S, Hwang L, Ng K, Trieu V
Received 8 January 2018
Accepted for publication 26 February 2018
Published 14 May 2018 Volume 2018:11 Pages 2779—2796
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Cristina Weinberg
Peer reviewer comments 2
Editor who approved publication: Dr Samir Farghaly
Osmond J D’Cruz,1 Sanjive Qazi,2 Larn Hwang,1,3 Kevin Ng,1 Vuong Trieu1,3
1Autotelic Inc, Costa Mesa, CA, USA; 2Biology Department, Gustavus Adolphus College, Saint Peter, MN, USA; 3Oncotelic Inc, Agoura Hills, CA, USA
Background: Overexpression of the cytokine – transforming growth factor-beta 2 (TGF-β2) – has been implicated in the malignant progression of pancreatic cancer (PAC). OT-101 (trabedersen) is an antisense oligodeoxynucleotide designed to target the human TGF-β2 mRNA. In a Phase I/II study, OT-101 treatment with subsequent chemotherapy was characterized by outstanding overall survival (OS) in patients with PAC.
Objective: This study sought to identify 1) co-regulated sets of cyto-/chemokines; 2) potential mechanisms that link TGF-β receptor type 2 receptor inhibition that may result in the induction of a cytokine storm; and 3) predictive biomarkers for OS outcome in OT-101-treated patients with PAC.
Materials and methods: Plasma levels of 31 cyto-/chemokines were tracked over three cycles of OT-101 therapy (140 mg/m2/day) in 12 PAC patients. Samples were acquired before onset of OT-101 therapy and at eight selected time points during therapy. A mixed ANCOVA model was developed for 19 cyto-/chemokines with median expression >1 following OT-101 therapy. Regression and hierarchical clustering analyses were performed to identify correlated expressions in each patient across cyto-/chemokines or in each cyto-/chemokine across patients. Plasma cyto-/chemokine levels were compared with OS with and without subsequent chemotherapy.
Results: Three highly correlated subsets of cyto-/chemokines (Cluster 1: EGF, MIP-1α, MIP-1β; Cluster 2: FGF-2, MIG, IP-10, IL-15, IFN-α, IL-12; and Cluster 3: HGF, IL-6, IL-8) were identified following OT-101 therapy. Suppression of TGF-β signaling by OT-101 led to upregulation of IL-8, IL-15, IP-10, and HGF. Protein–protein interaction networks constructed using STRING10 algorithm identified a relationship between IL-8, IL-15, and TGF-β receptor type 2 inhibition. The mixed analysis of covariance model that examined the levels of 19 cyto-/chemokines with OS as the covariate at each of the time points resulted in IL-8 and IL-15 exhibiting a significant association with OS during Cycle 1 of therapy. In the whole-blood culture model, the cytokines with the most pronounced increase after OT-101 treatment were IL-1β, IL-8, and MCP-1.
Conclusion: No consistent responses in cyto-/chemokine levels were observed due to OT-101 treatment. Levels of IL-8 and IL-15 during Cycle 1 were positively associated with OS across 12 patients with PAC and served as potential biomarkers for treatment outcome following OT-101 therapy.
Keywords: antisense oligonucleotides, biomarkers, cytokines, pancreatic cancer, survival, transforming growth factor-beta 2
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]