TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer
Galunisertib, the first small molecule transforming growth factor beta (TGFβ) receptor inhibitor, plus gemcitabine resulted in the improvement of survival in patients with unresectable pancreatic cancer, but markers to identify patients likely to respond are lacking.
In the Phase 1b/2 JBAJ study, 156 patients were randomized 2:1 to galunisertib + gemcitabine (N = 104) or placebo + gemcitabine (N = 52). Clinical outcome data were integrated with baseline markers and pharmacodynamic markers while patients were on treatment, including circulating proteins using a multi-analyte panel, T cell subset evaluation, and miRNA profiling.
Baseline biomarkers associated with overall prognosis regardless of treatment included CA19-9 and TGF-β1. In addition, IP-10, FSH, MIP-1α, and PAI-1 were potential predictive proteins. Baseline proteins that were changed during treatment included amphiregulin, CA15-3, cathepsin D, P-selectin, RAGE, sortilin, COMP, eotaxin-2, N-BNP, osteopontin, and thrombospondin-4. Plasma miRNA with potential prognostic value included miR-21-5p, miR-301a-3p, miR-210-3p, and miR-141-3p, while those with potential predictive value included miR-424-5p, miR-483-3p, and miR-10b-5p.
Galunisertib + gemcitabine resulted in improvement of overall survival, and 4 proteins (IP-10, FSH, MIP-1α, PAI-1) were potentially predictive for this combination treatment. Future studies should also include baseline evaluation of miR-424-5p, miR-483-3p, and miR-10b-5p.
KeywordsGalunisertib TGF-β1 CA19-9 Pancreatic cancer
The study team thanks patients and families for their willingness to participate in this study. We also thank all site staff and investigators at the institutions, and the trial personnel at Eli Lilly and Company and Covance. Work in the unit of the corresponding author was supported by the Investigator Grant no. 19111 through the Associazione Italiana per la Ricerca sul Cancro, Italy. Writing assistance was provided by Ananya Biswas (Eli Lilly Services India Pvt. Ltd., India).
This study was funded by Eli Lilly and Company, Indianapolis, Indiana, USA (Grant Number 230-0061-07472).
Compliance with ethical standards
Conflict of interest
Ann Cleverly, Ivelina Gueorguieva, Karim A. Benhadji, Shawn T. Estrem, Kyla Driscoll, and Michael Man are employees of Eli Lilly and Company, Indianapolis, Indiana, USA, and may hold company stock. Michael M. F. Lahn and Claire Smith are former employees of Eli Lilly and Company and hold company stock. Josep Tabernero has had an advisory role for Bayer, Boehringer Ingelheim, Genentech/Roche, Lilly, MSD, Merck Serono, Merrimack, Novartis, Peptomyc, Roche, Sanofi, Symphogen, and Taiho. Denis Pezet has had an advisory role for Sanofi, Novartis, and Roche.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 3.National Comprehensive Cancer Network (NCCN) (2016) NCCN clinical practice guidelines in oncology: Pancreatic adenocarcinoma v.1.2014. http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed Oct 2018
- 10.Kozloff M, Garcia-Carbonero R, Nadal T et al (2013) Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-β) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with gemcitabine in patients with advanced cancer. In: 2013 ASCO annual meeting, Chicago (J Clin Oncol 31(suppl; abstr 2563)) Google Scholar
- 17.Chiorean EG, Von Hoff DD, Reni M et al (2016) CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer. Ann Oncol 27(4):654–660CrossRefGoogle Scholar
- 21.Damaskos C, Garmpis N, Maratzas T et al (2014) Nuclear receptors in pancreatic tumor cells. Anticancer Res 34(12):6897–6911Google Scholar
- 33.Wei S, Li Q, Li Z, Wang L, Zhang L, Xu Z (2016) miR-424-5p promotes proliferation of gastric cancer by targeting Smad3 through TGF-β signaling pathway. Oncotarget 7(46):75185–75196Google Scholar
- 36.Yu Q, Xu C, Yuan W et al (2017) Evaluation of plasma micrornas as diagnostic and prognostic biomarkers in pancreatic adenocarcinoma: mir-196a and mir-210 could be negative and positive prognostic markers, respectively. Biomed Res Int 2017:6495867Google Scholar