TGFβ 受体抑制剂 galunisertib 与胰腺癌患者的炎症和重塑相关蛋白有关。

TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer.

机构信息

Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, Università degli studi di Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy.

University Hospital Doce de Octubre, Institute of Health Research Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain.

出版信息

Cancer Chemother Pharmacol. 2019 May;83(5):975-991. doi: 10.1007/s00280-019-03807-4. Epub 2019 Mar 18.

DOI:10.1007/s00280-019-03807-4

PMID:30887178

Abstract

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.

摘要

目的

加鲁钠昔布是首个小分子转化生长因子-β（TGFβ）受体抑制剂，联合吉西他滨可改善不可切除胰腺癌患者的生存，但缺乏识别可能受益于该治疗方案的患者的标志物。

方法

在 JBAJ 研究的 1b/2 期临床试验中，156 例患者按照 2:1 的比例随机分为加鲁钠昔布+吉西他滨组（N=104）或安慰剂+吉西他滨组（N=52）。整合了患者接受治疗时的临床结局数据与基线标志物和药效动力学标志物，包括使用多分析物面板检测循环蛋白、T 细胞亚群评估和 miRNA 谱分析。

结果

无论治疗方案如何，与总体预后相关的基线生物标志物包括 CA19-9 和 TGF-β1。此外，IP-10、FSH、MIP-1α 和 PAI-1 是潜在的预测蛋白。在治疗过程中发生变化的基线蛋白包括 Amphiregulin、CA15-3、组织蛋白酶 D、P-选择素、RAGE、Sortilin、COMP、Eotaxin-2、N-BNP、骨桥蛋白和血小板反应蛋白-4。具有潜在预后价值的血浆 miRNA 包括 miR-21-5p、miR-301a-3p、miR-210-3p 和 miR-141-3p，而具有潜在预测价值的 miRNA 包括 miR-424-5p、miR-483-3p 和 miR-10b-5p。