TY - JOUR
T1 - TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer
AU - Melisi, Davide
AU - Garcia-Carbonero, Rocio
AU - Macarulla, Teresa
AU - Pezet, Denis
AU - Deplanque, Gael
AU - Fuchs, Martin
AU - Trojan, Jorg
AU - Kozloff, Mark
AU - Simionato, Francesca
AU - Cleverly, Ann
AU - Smith, Claire
AU - Wang, Shuaicheng
AU - Man, Michael
AU - Driscoll, Kyla E.
AU - Estrem, Shawn T.
AU - Lahn, Michael M.F.
AU - Benhadji, Karim A.
AU - Tabernero, Josep
PY - 2019/1/1
Y1 - 2019/1/1
N2 - © 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: 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. Methods: 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. Results: 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. Conclusions: 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. Trial registration: Clinicaltrials.gov NCT01373164.
AB - © 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: 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. Methods: 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. Results: 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. Conclusions: 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. Trial registration: Clinicaltrials.gov NCT01373164.
KW - CA19-9
KW - Galunisertib
KW - Pancreatic cancer
KW - TGF-β1
U2 - 10.1007/s00280-019-03807-4
DO - 10.1007/s00280-019-03807-4
M3 - Article
C2 - 30887178
SN - 0344-5704
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
ER -
